View source for NMDA receptor

{{Short description|Glutamate receptor and ion channel protein found in nerve cells}}
{{Redirect|NR1|the submarine|NR-1}}
{{distinguish|NDMA (disambiguation)}}

[[File:Activated NMDAR.svg|right|thumb|Stylized depiction of an activated NMDAR. Glutamate is in the glutamate-binding site and glycine is in the glycine-binding site. The [[allosteric site]], which modulates receptor function when bound to a ligand, is not occupied. NMDARs require the binding of two molecules of [[glutamate]] or [[aspartate]] and two of [[glycine]]<ref name="Laube">{{cite journal | vauthors = Laube B, Hirai H, Sturgess M, Betz H, Kuhse J | title = Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit | journal = Neuron | volume = 18 | issue = 3 | pages = 493–503 | date = March 1997 | pmid = 9115742 | doi = 10.1016/S0896-6273(00)81249-0 | quote = Since two molecules of glutamate and glycine each are thought to be required for channel activation (3, 6), this implies that the NMDA receptor should be composed of at least four subunits. | doi-access = free }}</ref><ref name="Anson">{{cite journal | vauthors = Anson LC, Chen PE, Wyllie DJ, Colquhoun D, Schoepfer R | title = Identification of amino acid residues of the NR2A subunit that control glutamate potency in recombinant NR1/NR2A NMDA receptors | journal = The Journal of Neuroscience | volume = 18 | issue = 2 | pages = 581–589 | date = January 1998 | pmid = 9425000 | pmc = 6792534 | doi = 10.1523/JNEUROSCI.18-02-00581.1998 }}</ref>]]

The '''''N''-methyl-<small>D</small>-aspartate''' '''receptor''' (also known as the '''NMDA receptor''' or '''NMDAR'''), is a [[glutamate receptor]] and predominantly Ca<sup>2+</sup> [[ion channel]] found in [[neuron]]s.<ref>{{Cite journal |last1=Vyklicky |first1=V. |last2=Korinek |first2=M. |last3=Smejkalova |first3=T. |last4=Balik |first4=A. |last5=Krausova |first5=B. |last6=Kaniakova |first6=M. |last7=Lichnerova |first7=K. |last8=Cerny |first8=J. |last9=Krusek |first9=J. |last10=Dittert |first10=I. |last11=Horak |first11=M. |last12=Vyklicky |first12=L. |date=2014 |title=Structure, function, and pharmacology of NMDA receptor channels |journal=Physiological Research |volume=63 |issue=Suppl 1 |pages=S191–203 |doi=10.33549/physiolres.932678 |issn=1802-9973 |pmid=24564659|doi-access=free }}</ref><ref>{{Citation |last1=Jewett |first1=Benjamin E. |title=Physiology, NMDA Receptor |date=2024 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK519495/ |access-date=2024-03-04 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30137779 |last2=Thapa |first2=Bicky}}</ref> The NMDA receptor is one of three types of [[ionotropic glutamate receptor]]s, the other two being [[AMPA receptor|AMPA]] and [[kainate receptor]]s. Depending on its subunit composition, its [[Ligand (biochemistry)|ligands]] are [[Glutamate (neurotransmitter)|glutamate]] and [[glycine]] (or [[D-Serine|<small>D</small>-serine]]). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by [[Magnesium|Mg<sup>2+</sup>]] ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows [[cation|positively charged ions]] (cations) to flow through the [[cell membrane]].<ref name="Furukawa"/> The NMDA receptor is thought to be very important for controlling [[synaptic plasticity]] and mediating [[learning]] and [[memory]] functions.<ref name="pmid19605837">{{cite journal | vauthors = Li F, Tsien JZ | title = Memory and the NMDA receptors | journal = The New England Journal of Medicine | volume = 361 | issue = 3 | pages = 302–303 | date = July 2009 | pmid = 19605837 | pmc = 3703758 | doi = 10.1056/NEJMcibr0902052 }}</ref>

The NMDA receptor is [[ionotropic]], meaning it is a protein which allows the passage of ions through the cell membrane.<ref name="pmid1834949">{{cite journal | vauthors = Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S | title = Molecular cloning and characterization of the rat NMDA receptor | journal = Nature | volume = 354 | issue = 6348 | pages = 31–37 | date = November 1991 | pmid = 1834949 | doi = 10.1038/354031a0 | s2cid = 4368947 | bibcode = 1991Natur.354...31M }}</ref> The NMDA receptor is so named because the [[agonist]] molecule [[N-methyl-D-aspartate|''N''-methyl-<small>D</small>-aspartate]] (NMDA) binds selectively to it, and not to other [[glutamate receptor]]s. Activation of NMDA receptors results in the opening of the ion channel that is nonselective to [[ion|cations]], with a combined [[reversal potential]] near 0&nbsp;mV. While the opening and closing of the ion channel is primarily gated by ligand binding, the current flow through the ion channel is voltage-dependent. Specifically located on the receptor, extracellular magnesium (Mg<sup>2+</sup>) and zinc (Zn<sup>2+</sup>) ions can bind and prevent other cations from flowing through the open ion channel. A voltage-dependent flow of predominantly calcium (Ca<sup>2+</sup>), sodium (Na<sup>+</sup>), and potassium (K<sup>+</sup>) ions into and out of the cell is made possible by the depolarization of the cell, which displaces and repels the Mg<sup>2+</sup> and Zn<sup>2+</sup> ions from the pore.<ref name="pmid10049997">{{cite journal | vauthors = Dingledine R, Borges K, Bowie D, Traynelis SF | title = The glutamate receptor ion channels | journal = Pharmacological Reviews | volume = 51 | issue = 1 | pages = 7–61 | date = March 1999 | doi = 10.1016/S0031-6997(24)01394-2 | pmid = 10049997 | url = http://pharmrev.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10049997 | archive-date = 2020-10-27 | access-date = 2008-12-17 | archive-url = https://web.archive.org/web/20201027013532/https://pharmrev.aspetjournals.org/content/51/1/7.long | url-status = dead | url-access = subscription }}</ref><ref name="pmid11775847">{{cite journal | vauthors = Liu Y, Zhang J | title = Recent development in NMDA receptors | journal = Chinese Medical Journal | volume = 113 | issue = 10 | pages = 948–956 | date = October 2000 | pmid = 11775847 }}</ref><ref name="pmid11399431">{{cite journal | vauthors = Cull-Candy S, Brickley S, Farrant M | title = NMDA receptor subunits: diversity, development and disease | journal = Current Opinion in Neurobiology | volume = 11 | issue = 3 | pages = 327–335 | date = June 2001 | pmid = 11399431 | doi = 10.1016/S0959-4388(00)00215-4 | s2cid = 11929361 }}</ref><ref name="pmid17088105">{{cite journal | vauthors = Paoletti P, Neyton J | title = NMDA receptor subunits: function and pharmacology | journal = Current Opinion in Pharmacology | volume = 7 | issue = 1 | pages = 39–47 | date = February 2007 | pmid = 17088105 | doi = 10.1016/j.coph.2006.08.011 | url = https://hal.archives-ouvertes.fr/hal-00115220/file/PaolettiNeyton_Curr_Op_Pharmacol_main_text_020806.pdf }}</ref> Ca<sup>2+</sup> flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca<sup>2+</sup> ions.

Activity of the NMDA receptor is blocked by many [[psychoactive]] drugs such as [[phencyclidine]] (PCP), [[Alcohol (drug)|alcohol]] ([[ethanol]]) and [[dextromethorphan]] (DXM).<ref>{{Citation |last1=Journey |first1=Jonathan D. |title=Dextromethorphan Toxicity |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK538502/ |access-date=2025-03-25 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30860737 |last2=Agrawal |first2=Suneil |last3=Stern |first3=Evan}}</ref> The [[anaesthetic]] and [[analgesic]] effects of the drugs [[ketamine]] and [[nitrous oxide]] are also partially due to their effects at blocking NMDA receptor activity. In contrast, overactivation of NMDAR by NMDA agonists increases the [[cytosol]]ic concentrations of [[calcium]] and [[zinc]], which significantly contributes to [[Neuron|neural]] [[Neurodegeneration|death]], an effect known to be prevented by [[cannabinoid]]s, mediated by activation of the [[Cannabinoid receptor type 1|CB<sub>1</sub> receptor]], which leads [[HINT1]] protein to counteract the toxic effects of NMDAR-mediated [[Nitric oxide|NO]] production and zinc release.<ref>{{cite journal | vauthors = Sánchez-Blázquez P, Rodríguez-Muñoz M, Vicente-Sánchez A, Garzón J | title = Cannabinoid receptors couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced by glutamate | journal = Antioxidants & Redox Signaling | volume = 19 | issue = 15 | pages = 1766–1782 | date = November 2013 | pmid = 23600761 | pmc = 3837442 | doi = 10.1089/ars.2012.5100 }}</ref> As well as preventing [[methamphetamine]]-induced [[neurotoxicity]] via inhibition of [[nitric oxide synthase]] (nNOS) expression and [[astrocyte]] activation, it is seen to reduce methamphetamine induced brain damage through CB1-dependent and independent mechanisms, respectively, and inhibition of methamphetamine induced [[astrogliosis]] is likely to occur through a [[Cannabinoid receptor type 2|CB<sub>2</sub> receptor]] dependent mechanism for [[Tetrahydrocannabinol|THC]].<ref>{{cite journal | vauthors = Castelli MP, Madeddu C, Casti A, Casu A, Casti P, Scherma M, Fattore L, Fadda P, Ennas MG | display-authors = 6 | title = Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity | journal = PLOS ONE | volume = 9 | issue = 5 | pages = e98079 | date = 2014-05-20 | pmid = 24844285 | pmc = 4028295 | doi = 10.1371/journal.pone.0098079 | doi-access = free | bibcode = 2014PLoSO...998079C }}</ref> Since 1989, [[memantine]] has been recognized to be an [[uncompetitive antagonist]] of the NMDA receptor, entering the channel of the receptor after it has been activated and thereby blocking the flow of ions.<ref name="Johnson">{{cite journal | vauthors = Johnson JW, Kotermanski SE | title = Mechanism of action of memantine | journal = Current Opinion in Pharmacology | volume = 6 | issue = 1 | pages = 61–67 | date = February 2006 | pmid = 16368266 | doi = 10.1016/j.coph.2005.09.007 }}</ref><ref name="Dominguez">{{cite journal | vauthors = Dominguez E, Chin TY, Chen CP, Wu TY | title = Management of moderate to severe Alzheimer's disease: focus on memantine | journal = Taiwanese Journal of Obstetrics & Gynecology | volume = 50 | issue = 4 | pages = 415–423 | date = December 2011 | pmid = 22212311 | doi = 10.1016/j.tjog.2011.10.004 | doi-access = free }}</ref><ref name="Chen">{{cite journal | vauthors = Chen HS, Lipton SA | title = The chemical biology of clinically tolerated NMDA receptor antagonists | journal = Journal of Neurochemistry | volume = 97 | issue = 6 | pages = 1611–1626 | date = June 2006 | pmid = 16805772 | doi = 10.1111/j.1471-4159.2006.03991.x | s2cid = 18376541 | doi-access = free }}</ref>

Overactivation of the receptor, causing excessive influx of Ca<sup>2+</sup> can lead to [[excitotoxicity]] which is implied to be involved in some neurodegenerative disorders. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.<ref name="Chen" /><ref name="Kemp">{{cite journal | vauthors = Kemp JA, McKernan RM | title = NMDA receptor pathways as drug targets | journal = Nature Neuroscience | volume = 5 | issue = 11 | pages = 1039–1042 | date = November 2002 | pmid = 12403981 | doi = 10.1038/nn936 | s2cid = 41383776 }}</ref><ref name="Lipton1">{{cite journal | vauthors = Lipton SA | title = Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond | journal = Nature Reviews. Drug Discovery | volume = 5 | issue = 2 | pages = 160–170 | date = February 2006 | pmid = 16424917 | doi = 10.1038/nrd1958 | s2cid = 21379258 }}</ref><ref name="Koch">{{cite journal | vauthors = Koch HJ, Szecsey A, Haen E | title = NMDA-antagonism (memantine): an alternative pharmacological therapeutic principle in Alzheimer's and vascular dementia | journal = Current Pharmaceutical Design | volume = 10 | issue = 3 | pages = 253–259 | date = 1 January 2004 | pmid = 14754385 | doi = 10.2174/1381612043386392 }}</ref> However, hypofunction of NMDA receptors (due to [[glutathione]] deficiency or other causes) may be involved in impairment of synaptic plasticity<ref name="pmid16330153">{{cite journal | vauthors = Steullet P, Neijt HC, Cuénod M, Do KQ | title = Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia | journal = Neuroscience | volume = 137 | issue = 3 | pages = 807–819 | date = February 2006 | pmid = 16330153 | doi = 10.1016/j.neuroscience.2005.10.014 | s2cid = 1417873 }}</ref> and could have other negative repercussions. The main problem with the utilization of [[NMDA receptor antagonist]]s for [[neuroprotection]] is that the physiological actions of the NMDA receptor are essential for normal neuronal function. To be clinically useful NMDA antagonists need to block excessive activation without interfering with normal functions. [[Memantine]] has this property.<ref name="Lipton2">{{cite journal | vauthors = Lipton SA | title = Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults | journal = NeuroRx | volume = 1 | issue = 1 | pages = 101–110 | date = January 2004 | pmid = 15717010 | pmc = 534915 | doi = 10.1602/neurorx.1.1.101 }}</ref>

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== History ==
The discovery of NMDA receptors was followed by the synthesis and study of ''N''-methyl-<small>D</small>-aspartic acid (NMDA) in the 1960s by [[Jeff Watkins]] and colleagues. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways.<ref name="Cheng">{{cite journal | vauthors = Yamakura T, Shimoji K | title = Subunit- and site-specific pharmacology of the NMDA receptor channel | journal = Progress in Neurobiology | volume = 59 | issue = 3 | pages = 279–298 | date = October 1999 | pmid = 10465381 | doi = 10.1016/S0301-0082(99)00007-6 | s2cid = 24726102 }}</ref><ref name="Watkins">{{cite journal | vauthors = Watkins JC, Jane DE | title = The glutamate story | journal = British Journal of Pharmacology | volume = 147 | issue = S1 | pages = S100–S108 | date = January 2006 | pmid = 16402093 | pmc = 1760733 | doi = 10.1038/sj.bjp.0706444 }}</ref> Receptor subunit selectivity was discovered in the early 1990s, which led to recognition of a new class of compounds that selectively inhibit the [[NR2B]] subunit. These findings led to vigorous campaign in the pharmaceutical industry.<ref name="pmid17088105"/> From this it was considered that NMDA receptors were associated with a variety of [[neurological disorders]] such as [[epilepsy]], [[Parkinson's disease|Parkinson's]], [[Alzheimer's disease|Alzheimer's]], [[Huntington's disease|Huntington's]] and other CNS disorders.<ref name="pmid10049997"/>

In 2002, it was discovered by [[Hilmar Bading]] and co-workers that the cellular consequences of NMDA receptor stimulation depend on the receptor's location on the neuronal cell surface.<ref name="pmid11953750">{{cite journal | vauthors = Hardingham GE, Fukunaga Y, Bading H | title = Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways | journal = Nature Neuroscience | volume = 5 | issue = 5 | pages = 405–414 | date = May 2002 | pmid = 11953750 | doi = 10.1038/nn835 | s2cid = 659716 }}</ref><ref name=":4">{{cite journal | vauthors = Hardingham GE, Bading H | title = Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders | journal = Nature Reviews. Neuroscience | volume = 11 | issue = 10 | pages = 682–696 | date = October 2010 | pmid = 20842175 | pmc = 2948541 | doi = 10.1038/nrn2911 }}</ref> Synaptic NMDA receptors promote gene expression, plasticity-related events, and acquired [[neuroprotection]]. Extrasynaptic NMDA receptors promote death signaling; they cause transcriptional shut-off, mitochondrial dysfunction, and structural disintegration.<ref name="pmid11953750"/><ref name=":4" /> This pathological triad of extrasynaptic NMDA receptor signaling represents a common conversion point in the etiology of several acute and chronic neurodegenerative conditions.<ref>{{cite journal | vauthors = Bading H | title = Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations | journal = The Journal of Experimental Medicine | volume = 214 | issue = 3 | pages = 569–578 | date = March 2017 | pmid = 28209726 | pmc = 5339681 | doi = 10.1084/jem.20161673 }}</ref> The molecular basis for toxic extrasynaptic NMDA receptor signaling was uncovered by Hilmar Bading and co-workers in 2020.<ref name=":5">{{cite journal | vauthors = Yan J, Bengtson CP, Buchthal B, Hagenston AM, Bading H | title = Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants | journal = Science | volume = 370 | issue = 6513 | pages = eaay3302 | date = October 2020 | pmid = 33033186 | doi = 10.1126/science.aay3302 | s2cid = 222210921 }}</ref> [[Extrasynaptic NMDA receptors]] form a death signaling complex with TRPM4. NMDAR/TRPM4 interaction interface inhibitors (also known as interface inhibitors) disrupt the NMDAR/TRPM4 complex and detoxify extrasynaptic NMDA receptors.<ref name=":5" />

A fortuitous finding was made in 1968 when a woman was taking [[amantadine]] as flu medicine and experienced remarkable remission of her Parkinson's symptoms. This finding, reported by Scawab et al., was the beginning of [[medicinal chemistry]] of adamantane derivatives in the context of diseases affecting the CNS.<ref name="Wanka">{{cite journal | vauthors = Wanka L, Iqbal K, Schreiner PR | title = The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives | journal = Chemical Reviews | volume = 113 | issue = 5 | pages = 3516–3604 | date = May 2013 | pmid = 23432396 | pmc = 3650105 | doi = 10.1021/cr100264t }}</ref> Before this finding, memantine, another adamantane derivative, had been synthesized by Eli Lilly and Company in 1963. The purpose was to develop a [[hypoglycemic]] drug, but it showed no such [[efficacy]]. It was not until 1972 that a possible therapeutic importance of memantine for treating neurodegenerative disorders was discovered. From 1989 memantine has been recognized to be an uncompetitive antagonist of the NMDA receptor.<ref name="Dominguez" />

== Structure ==

[[File:7eu7 NMDA-Rezeptor Regenbogen.png|right|thumb|Three dimensional representation of the human NMDA receptor. Each subunit is individually rainbow colored.]]

Functional NMDA receptors are heterotetramers comprising different combinations of the GluN1, GluN2 (A-D), and GluN3 (A-B) subunits derived from distinct gene families (''Grin1''-''Grin3''). All NMDARs contain two of the obligatory GluN1 subunits, which when assembled with GluN2 subunits of the same type, give rise to canonical diheteromeric (''d''-) NMDARs (e.g., GluN1-2A-1-2A). Triheteromeric NMDARs, by contrast, contain three different types of subunits (e.g., GluN1-2A-1-2B), and include receptors that are composed of one or more subunits from each of the three gene families, designated ''t''-NMDARs (e.g., GluN1-2A-3A-2A).<ref>{{cite journal | vauthors = Beesley S, Kumar SS | title = The t-N-methyl-d-aspartate receptor: Making the case for d-Serine to be considered its inverse co-agonist | journal = Neuropharmacology | volume = 238 | pages = 109654 | date = November 2023 | pmid = 37437688 | doi = 10.1016/j.neuropharm.2023.109654 | doi-access = free }}</ref> There is one GluN1, four GluN2, and two GluN3 subunit encoding genes, and each gene may produce more than one splice variant.
* GluN1 – [[GRIN1]]
* GluN2
** GluN2A – [[GRIN2A]]
** GluN2B – [[GRIN2B]]
** GluN2C – [[GRIN2C]]
** GluN2D – [[GRIN2D]]
* GluN3
** GluN3A – [[GRIN3A]]
** GluN3B – [[GRIN3B]]

== Gating ==
[[File:N1 N2 NMDA receptor.svg|thumb|400px|'''Figure 1:''' NR1/NR2 NMDA receptor]]
The NMDA receptor is a [[Glutamic acid|glutamate]] and [[ion channel]] protein receptor that is activated when [[glycine]] and glutamate bind to it.<ref name="Furukawa">{{cite journal | vauthors = Furukawa H, Singh SK, Mancusso R, Gouaux E | title = Subunit arrangement and function in NMDA receptors | journal = Nature | volume = 438 | issue = 7065 | pages = 185–192 | date = November 2005 | pmid = 16281028 | doi = 10.1038/nature04089 | s2cid = 4400777 | bibcode = 2005Natur.438..185F }}</ref> The receptor is a highly complex and dynamic heteromeric protein that interacts with a multitude of intracellular [[protein]]s via three distinct subunits, namely GluN1, GluN2, and GluN3. The GluN1 subunit, which is encoded by the GRIN1 gene, exhibits eight distinct isoforms owing to alternative splicing. On the other hand, the GluN2 subunit, of which there are four different types (A-D), as well as the GluN3 subunit, of which there are two types (A and B), are each encoded by six separate genes. This intricate molecular structure and genetic diversity enable the receptor to carry out a wide range of physiological functions within the [[nervous system]].<ref name="Loftis">{{cite journal | vauthors = Loftis JM, Janowsky A | title = The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications | journal = Pharmacology & Therapeutics | volume = 97 | issue = 1 | pages = 55–85 | date = January 2003 | pmid = 12493535 | doi = 10.1016/s0163-7258(02)00302-9 }}</ref><ref name="Kristiansen">{{cite journal | vauthors = Kristiansen LV, Huerta I, Beneyto M, Meador-Woodruff JH | title = NMDA receptors and schizophrenia | journal = Current Opinion in Pharmacology | volume = 7 | issue = 1 | pages = 48–55 | date = February 2007 | pmid = 17097347 | doi = 10.1016/j.coph.2006.08.013 }}</ref> All the subunits share a common membrane topology that is dominated by a large extracellular N-terminus, a membrane region comprising three transmembrane segments, a re-entrant pore loop, an extracellular loop between the transmembrane segments that are structurally not well known, and an intracellular C-terminus, which are different in size depending on the subunit and provide multiple sites of interaction with many intracellular proteins.<ref name="Loftis" /><ref name="Limapichat">{{cite journal | vauthors = Limapichat W, Yu WY, Branigan E, Lester HA, Dougherty DA | title = Key binding interactions for memantine in the NMDA receptor | journal = ACS Chemical Neuroscience | volume = 4 | issue = 2 | pages = 255–260 | date = February 2013 | pmid = 23421676 | pmc = 3751542 | doi = 10.1021/cn300180a }}</ref> Figure 1 shows a basic structure of GluN1/GluN2 subunits that forms the [[binding site]] for memantine, Mg<sup>2+</sup> and [[ketamine]].
[[File:NR1-NR2B subunit.png|thumb|270px|'''Figure 2:''' Transmembrane region of NR1 (left) and NR2B (right) subunits of NMDA receptor|left]]
Mg<sup>2+</sup> blocks the NMDA receptor channel in a voltage-dependent manner. The channels are also highly permeable to Ca<sup>2+</sup>. Activation of the receptor depends on glutamate binding, [[D-Serine|<small>D</small>-serine]] or glycine binding at its GluN1-linked binding site  and  [[AMPA receptor]]-mediated [[depolarization]] of the postsynaptic membrane, which relieves the voltage-dependent channel block by Mg<sup>2+</sup>. Activation and opening of the receptor channel thus allows the flow of K<sup>+</sup>, Na<sup>+</sup> and Ca<sup>2+</sup> ions, and the influx of Ca<sup>2+</sup> triggers intracellular signaling pathways.<ref name="Johnson" /><ref name="Maher">{{cite book | vauthors = Maher TJ | date = 2013 | chapter = Chapter 16: Anesthetic agents: General and local anesthetics. | chapter-url = https://downloads.lww.com/wolterskluwer_vitalstream_com/sample-content/9781609133450_Lemke/samples/Chapter_16.pdf | veditors = Lemke TL, Williams DA | title = Foye's Principles of Medicinal Chemistry | location = Philadelphia | publisher = Lippincott Williams & Wilkins | isbn = 978-1-60913-345-0 }}</ref> Allosteric receptor binding sites for zinc, proteins and the polyamines spermidine and spermine are also modulators for the NMDA receptor channels.<ref name="Danysz">{{cite journal | vauthors = Danysz W, Parsons CG | title = The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence | journal = International Journal of Geriatric Psychiatry | volume = 18 | issue = Suppl 1 | pages = S23–S32 | date = September 2003 | pmid = 12973747 | doi = 10.1002/gps.938 | s2cid = 14852616 }}</ref>

The GluN2B subunit has been involved in modulating activity such as learning, memory, processing and feeding behaviors, as well as being implicated in number of human derangements. The basic structure and functions associated with the NMDA receptor can be attributed to the GluN2B subunit. For example, the glutamate binding site and the control of the Mg<sup>2+</sup> block are formed by the GluN2B subunit. The high affinity sites for glycine [[antagonist]] are also exclusively displayed by the GluN1/GluN2B receptor.<ref name="Kristiansen" />

GluN1/GluN2B transmembrane segments are considered to be the part of the receptor that forms the binding pockets for uncompetitive NMDA receptor antagonists, but the transmembrane segments structures are not fully known as stated above. It is claimed that three binding sites within the receptor, A644 on the GluNB subunit and A645 and N616 on the GluN1 subunit, are important for binding of memantine and related compounds as seen in figure 2.<ref name="Limapichat" />

The NMDA receptor forms a [[heterotetramer]] between two GluN1 and two GluN2 subunits (the subunits were previously denoted as GluN1 and GluN2), two obligatory GluN1 subunits and two regionally localized GluN2 subunits. A related [[gene]] family of GluN3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor [[isoform]]s with distinct brain distributions and functional properties arise by selective splicing of the GluN1 transcripts and differential expression of the GluN2 subunits.

Each receptor subunit has modular design and each structural module, also represents a functional unit:
* The ''[[extracellular]] [[Protein domain|domain]]'' contains two globular structures: a modulatory domain and a [[ligand]]-binding domain. GluN1 subunits bind the co-agonist glycine and GluN2 subunits bind the neurotransmitter glutamate.<ref name="Laube" /><ref name="Anson" />
* The ''agonist-binding module'' links to a membrane domain, which consists of three transmembrane segments and a re-entrant loop reminiscent of the selectivity filter of [[potassium channels]].
* The ''membrane domain'' contributes residues to the channel pore and is responsible for the receptor's high-unitary [[Electrical conductance|conductance]], high-calcium permeability, and voltage-dependent magnesium block.
* Each subunit has an extensive ''cytoplasmic domain'', which contain residues that can be directly modified by a series of [[protein kinases]] and [[protein phosphatases]], as well as residues that interact with a large number of structural, adaptor, and scaffolding proteins.

The glycine-binding modules of the GluN1 and GluN3 subunits and the glutamate-binding module of the GluN2A subunit have been expressed as soluble proteins, and their three-dimensional structure has been solved at atomic resolution by [[x-ray crystallography]]. This has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors and kainate-receptors.

== Mechanism of action ==
NMDA receptors are a crucial part of the development of the central nervous system. The processes of learning, memory, and [[neuroplasticity]] rely on the mechanism of NMDA receptors. NMDA receptors are glutamate-gated cation channels that allow for an increase of calcium [[Permeability (Earth sciences)|permeability]]. Channel activation of NMDA receptors is a result of the binding of two co agonists, [[glycine]] and [[glutamate]].

Overactivation of NMDA receptors, causing excessive influx of Ca<sup>2+</sup> can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.<ref name="Chen" /><ref name="Kemp" /><ref name="Lipton1" /><ref name="Koch" /> Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.<ref name="Chen" /><ref name="Kemp" /><ref name="Lipton1" /> It is, however, important to preserve physiological NMDA receptor activity while trying to block its excessive, excitotoxic activity. This can possibly be achieved by uncompetitive antagonists, blocking the receptors ion channel when excessively open.<ref name="Lipton1" />

Uncompetitive NMDA receptor antagonists, or channel blockers, enter the channel of the NMDA receptor after it has been activated and thereby block the flow of ions.<ref name="Johnson" /><ref name="Chen" /> [[MK-801]], [[ketamine]], [[amantadine]] and [[memantine]] are examples of such antagonists,<ref name="Johnson" /> see figure 1. The off-rate of an antagonist from the receptors channel is an important factor as too slow off-rate can interfere with normal function of the receptor and too fast off-rate may give ineffective blockade of an excessively open receptor.<ref name="Lipton1" />

[[Memantine]] is an example of an uncompetitive channel blocker of the NMDA receptor, with a relatively rapid off-rate and low affinity. At physiological pH its amine group is positively charged and its receptor antagonism is voltage-dependent.<ref name="Lipton1" /> It thereby mimics the physiological function of Mg<sup>2+</sup> as channel blocker.<ref name="Dominguez" /> Memantine only blocks NMDA receptor associated channels during prolonged activation of the receptor, as it occurs under excitotoxic conditions, by replacing magnesium at the binding site. During normal receptor activity the channels only stay open for several milliseconds and under those circumstances memantine is unable to bind within the channels and therefore does not interfere with normal synaptic activity.<ref name="Lipton2" />

==Variants==

===GluN1===
There are eight variants of the [[GRIN1|GluN1]] subunit produced by alternative splicing of [[GRIN1]]:<ref name="Stephenson_2006">{{cite journal | vauthors = Stephenson FA | title = Structure and trafficking of NMDA and GABAA receptors | journal = Biochemical Society Transactions | volume = 34 | issue = Pt 5 | pages = 877–881 | date = November 2006 | pmid = 17052219 | doi = 10.1042/BST0340877 | s2cid = 24875113 }}</ref>
* GluN1-1a, GluN1-1b; GluN1-1a is the most abundantly expressed form.
* GluN1-2a, GluN1-2b;
* GluN1-3a, GluN1-3b;
* GluN1-4a, GluN1-4b;

===GluN2===
[[File:Model of NR2 Subunit of NMDA receptor (vertebrate and invertebrate).jpg|thumb|NR2 subunit in vertebrates (left) and invertebrates (right). Ryan et al., 2008]]
While a single GluN2 subunit is found in [[invertebrate]] [[organism]]s, four distinct isoforms of the GluN2 subunit are expressed in [[vertebrate]]s and are referred to with the nomenclature GluN2A through GluN2D (encoded by [[GRIN2A]], [[GRIN2B]], [[GRIN2C]], [[GRIN2D]]). Strong evidence shows that the genes encoding the GluN2 subunits in vertebrates have undergone at least two rounds of [[gene duplication]].<ref name="pmid20976280">
{{cite journal | vauthors = Teng H, Cai W, Zhou L, Zhang J, Liu Q, Wang Y, Dai W, Zhao M, Sun Z | display-authors = 6 | title = Evolutionary mode and functional divergence of vertebrate NMDA receptor subunit 2 genes | journal = PLOS ONE | volume = 5 | issue = 10 | pages = e13342 | date = October 2010 | pmid = 20976280 | pmc = 2954789 | doi = 10.1371/journal.pone.0013342 | doi-access = free | bibcode = 2010PLoSO...513342T }}</ref> They contain the binding-site for [[glutamate]]. More importantly, each GluN2 subunit has a different intracellular C-terminal domain that can interact with different sets of signaling molecules.<ref name="Ryan2009">{{cite journal | vauthors = Ryan TJ, Grant SG | title = The origin and evolution of synapses | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 10 | pages = 701–712 | date = October 2009 | pmid = 19738623 | doi = 10.1038/nrn2717 | s2cid = 5164419 }}</ref> Unlike GluN1 subunits, GluN2 subunits are expressed differentially across various cell types and developmental timepoints and control the electrophysiological properties of the NMDA receptor. In classic circuits, GluN2B is mainly present in immature neurons and in extrasynaptic locations such as [[growth cone]]s,<ref name="Georgiev2008">{{cite journal | vauthors = Georgiev D, Taniura H, Kambe Y, Takarada T, Yoneda Y | title = A critical importance of polyamine site in NMDA receptors for neurite outgrowth and fasciculation at early stages of P19 neuronal differentiation | journal = Experimental Cell Research | volume = 314 | issue = 14 | pages = 2603–2617 | date = August 2008 | pmid = 18586028 | doi = 10.1016/j.yexcr.2008.06.009 }}</ref> and contains the binding-site for the selective inhibitor [[ifenprodil]].<ref name="Bunk2014">{{cite journal | vauthors = Bunk EC, König HG, Prehn JH, Kirby BP | title = Effect of the N-methyl-D-aspartate NR2B subunit antagonist ifenprodil on precursor cell proliferation in the hippocampus | journal = Journal of Neuroscience Research | volume = 92 | issue = 6 | pages = 679–691 | date = June 2014 | pmid = 24464409 | doi = 10.1002/jnr.23347 | s2cid = 18582691 | url = https://figshare.com/articles/journal_contribution/10798256 }}</ref> However, in [[pyramidal cell]] [[synapse]]s in the newly evolved primate [[dorsolateral prefrontal cortex]], GluN2B are exclusively within the [[postsynaptic density]], and mediate higher cognitive operations such as [[working memory]].<ref name="Wang2013">{{cite journal | vauthors = Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang XJ, Arnsten AF | display-authors = 6 | title = NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex | journal = Neuron | volume = 77 | issue = 4 | pages = 736–749 | date = February 2013 | pmid = 23439125 | pmc = 3584418 | doi = 10.1016/j.neuron.2012.12.032 }}</ref> This is consistent with the expansion in GluN2B actions and expression across the cortical hierarchy in [[monkey]]s <ref name="Yang2018">{{cite journal | vauthors = Yang ST, Wang M, Paspalas CD, Crimins JL, Altman MT, Mazer JA, Arnsten AF | title = Core Differences in Synaptic Signaling Between Primary Visual and Dorsolateral Prefrontal Cortex | journal = Cerebral Cortex | volume = 28 | issue = 4 | pages = 1458–1471 | date = April 2018 | pmid = 29351585 | pmc = 6041807 | doi = 10.1093/cercor/bhx357 }}</ref> and [[human]]s <ref name="Burt2018">{{cite journal | vauthors = Burt JB, Demirtaş M, Eckner WJ, Navejar NM, Ji JL, Martin WJ, Bernacchia A, Anticevic A, Murray JD | display-authors = 6 | title = Hierarchy of transcriptomic specialization across human cortex captured by structural neuroimaging topography | journal = Nature Neuroscience | volume = 21 | issue = 9 | pages = 1251–1259 | date = September 2018 | pmid = 30082915 | pmc = 6119093 | doi = 10.1038/s41593-018-0195-0 }}</ref> and across [[primate]] [[cerebral cortex|cortex]] [[evolution]].<ref name="Muntane2015">{{cite journal | vauthors = Muntané G, Horvath JE, Hof PR, Ely JJ, Hopkins WD, Raghanti MA, Lewandowski AH, Wray GA, Sherwood CC | display-authors = 6 | title = Analysis of synaptic gene expression in the neocortex of primates reveals evolutionary changes in glutamatergic neurotransmission | journal = Cerebral Cortex | volume = 25 | issue = 6 | pages = 1596–1607 | date = June 2015 | pmid = 24408959 | pmc = 4428301 | doi = 10.1093/cercor/bht354 }}</ref>

===GluN2B to GluN2A switch===
[[File: NR2B-NR2A switch in human cerebellum, microarrays, Bar-Shira et al 2015.png| thumb|The timecourse of GluN2B-GluN2A switch in human cerebellum. Bar-Shira et al., 2015 <ref name="pmid26636753">{{cite journal | vauthors = Bar-Shira O, Maor R, Chechik G | title = Gene Expression Switching of Receptor Subunits in Human Brain Development | journal = PLOS Computational Biology | volume = 11 | issue = 12 | pages = e1004559 | date = December 2015 | pmid = 26636753 | pmc = 4670163 | doi = 10.1371/journal.pcbi.1004559 | bibcode = 2015PLSCB..11E4559B | doi-access = free }}</ref>]]

While [[GRIN2B|GluN2B]] is predominant in the early postnatal brain, the number of GluN2A subunits increases during early development; eventually, [[GRIN2A|GluN2A]] subunits become more numerous than GluN2B. This is called the GluN2B-GluN2A developmental switch, and is notable because of the different kinetics each GluN2 subunit contributes to receptor function.<ref name="pmid15470155">
{{cite journal | vauthors = Liu XB, Murray KD, Jones EG | title = Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development | journal = The Journal of Neuroscience | volume = 24 | issue = 40 | pages = 8885–8895 | date = October 2004 | pmid = 15470155 | pmc = 6729956 | doi = 10.1523/JNEUROSCI.2476-04.2004 }}</ref> For instance, greater ratios of the GluN2B subunit leads to NMDA receptors which remain open longer compared to those with more GluN2A.<ref name="pmid10789248">{{cite journal | vauthors = Tsien JZ | title = Building a brainier mouse | journal = Scientific American | volume = 282 | issue = 4 | pages = 62–68 | date = April 2000 | pmid = 10789248 | doi = 10.1038/scientificamerican0400-62 | bibcode = 2000SciAm.282d..62T }}</ref> This may in part account for greater memory abilities in the immediate postnatal period compared to late in life, which is the principle behind genetically altered '[[doogie mice]]'.
The detailed time course of this switch in the human cerebellum has been estimated using expression microarray and RNA seq and is shown in the figure on the right.

There are three hypothetical models to describe this switch mechanism:
* Increase in synaptic GluN2A along with decrease in GluN2B
* Extrasynaptic displacement of GluN2B away from the synapse with increase in GluN2A
* Increase of GluN2A diluting the number of GluN2B without the decrease of the latter.

The GluN2B and GluN2A subunits also have differential roles in mediating [[excitotoxicity|excitotoxic]] neuronal death.<ref name="pmid17360906">{{cite journal | vauthors = Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT | display-authors = 6 | title = NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo | journal = The Journal of Neuroscience | volume = 27 | issue = 11 | pages = 2846–2857 | date = March 2007 | pmid = 17360906 | pmc = 6672582 | doi = 10.1523/JNEUROSCI.0116-07.2007 }}</ref> The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.<ref name="pmid16540573">{{cite journal | vauthors = Zhou M, Baudry M | title = Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors | journal = The Journal of Neuroscience | volume = 26 | issue = 11 | pages = 2956–2963 | date = March 2006 | pmid = 16540573 | pmc = 6673978 | doi = 10.1523/JNEUROSCI.4299-05.2006 }}</ref> Homozygous disruption of the gene for GluN2B in mice causes perinatal [[lethality]], whereas disruption of the GluN2A gene produces viable mice, although with impaired hippocampal plasticity.<ref>{{cite journal | vauthors = Sprengel R, Suchanek B, Amico C, Brusa R, Burnashev N, Rozov A, Hvalby O, Jensen V, Paulsen O, Andersen P, Kim JJ, Thompson RF, Sun W, Webster LC, Grant SG, Eilers J, Konnerth A, Li J, McNamara JO, Seeburg PH | display-authors = 6 | title = Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo | journal = Cell | volume = 92 | issue = 2 | pages = 279–289 | date = January 1998 | pmid = 9458051 | doi = 10.1016/S0092-8674(00)80921-6 | s2cid = 9791935 | doi-access = free }}</ref> One study suggests that [[reelin]] may play a role in the NMDA receptor maturation by increasing the GluN2B subunit mobility.<ref name="pmid17881522">{{cite journal | vauthors = Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P | title = NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin | journal = The Journal of Neuroscience | volume = 27 | issue = 38 | pages = 10165–10175 | date = September 2007 | pmid = 17881522 | pmc = 6672660 | doi = 10.1523/JNEUROSCI.1772-07.2007 }}</ref>

===GluN2B to GluN2C switch===
Granule cell precursors (GCPs) of the cerebellum, after undergoing symmetric cell division<ref name="pmid18322077">{{cite journal | vauthors = Espinosa JS, Luo L | title = Timing neurogenesis and differentiation: insights from quantitative clonal analyses of cerebellar granule cells | journal = The Journal of Neuroscience | volume = 28 | issue = 10 | pages = 2301–2312 | date = March 2008 | pmid = 18322077 | pmc = 2586640 | doi = 10.1523/JNEUROSCI.5157-07.2008 }}</ref> in the external granule-cell layer (EGL), migrate into the internal granule-cell layer (IGL) where they down-regulate GluN2B and activate GluN2C, a process that is independent of neuregulin beta signaling through ErbB2 and ErbB4 receptors.<ref name="pmid19244516">{{cite journal | vauthors = Gajendran N, Kapfhammer JP, Lain E, Canepari M, Vogt K, Wisden W, Brenner HR | title = Neuregulin signaling is dispensable for NMDA- and GABA(A)-receptor expression in the cerebellum in vivo | journal = The Journal of Neuroscience | volume = 29 | issue = 8 | pages = 2404–2413 | date = February 2009 | pmid = 19244516 | pmc = 6666233 | doi = 10.1523/JNEUROSCI.4303-08.2009 }}</ref>

==Role in excitotoxicity==
<!-- Deleted image removed: [[File:Animation of Excitotoxicity using NMDA Receptors.gif|right]] -->
NMDA receptors have been implicated by a number of studies to be strongly involved with [[excitotoxicity]].<ref name=":0" /><ref name="pmid2892896">{{cite journal | vauthors = Choi DW, Koh JY, Peters S | title = Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists | journal = The Journal of Neuroscience | volume = 8 | issue = 1 | pages = 185–196 | date = January 1988 | pmid = 2892896 | pmc = 6569373 | doi = 10.1523/JNEUROSCI.08-01-00185.1988 }}</ref><ref>{{Cite book|title=Handbook of Clinical Neurology| vauthors = Henchcliffe C |publisher=Weill Medical College of Cornell University, Department of Neurology and Neuroscience|year=2007|location=New York, NY, USA|pages=553–569}}</ref> Because NMDA receptors play an important role in the health and function of [[neuron]]s, there has been much discussion on how these receptors can affect both cell survival and cell death.<ref name=":2">{{cite journal | vauthors = Hardingham GE, Bading H | title = The Yin and Yang of NMDA receptor signalling | journal = Trends in Neurosciences | volume = 26 | issue = 2 | pages = 81–89 | date = February 2003 | pmid = 12536131 | doi = 10.1016/s0166-2236(02)00040-1 | s2cid = 26207057 }}</ref> Recent evidence supports the hypothesis that overstimulation of [[extrasynaptic NMDA receptor]]s has more to do with excitotoxicity than stimulation of their [[Synapse|synaptic]] counterparts.<ref name=":0" /><ref name="pmid11953750"/> In addition, while stimulation of [[extrasynaptic NMDA receptor]]s appear to contribute to cell death, there is evidence to suggest that stimulation of synaptic NMDA receptors contributes to the health and longevity of the cell. There is ample evidence to support the dual nature of NMDA receptors based on location, and the hypothesis explaining the two differing mechanisms is known as the "localization hypothesis".<ref name=":0" /><ref name=":2" />

===Differing cascade pathways===
In order to support the localization hypothesis, it would be necessary to show differing [[Cell signaling|cellular signaling pathways]] are activated by NMDA receptors based on its location within the cell membrane.<ref name=":0" /> Experiments have been designed to stimulate either synaptic or non-synaptic NMDA receptors exclusively. These types of experiments have shown that different pathways are being activated or regulated depending on the location of the signal origin.<ref name="pmid20720132">{{cite journal | vauthors = Xia P, Chen HS, Zhang D, Lipton SA | title = Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses | journal = The Journal of Neuroscience | volume = 30 | issue = 33 | pages = 11246–11250 | date = August 2010 | pmid = 20720132 | pmc = 2932667 | doi = 10.1523/JNEUROSCI.2488-10.2010 }}</ref> Many of these pathways use the same [[Protein targeting|protein signals]], but are regulated oppositely by NMDARs depending on its location. For example, synaptic NMDA excitation caused a decrease in the intracellular concentration of p38 mitogen-activated protein kinase ([[p38 mitogen-activated protein kinases|p38MAPK]]). Extrasynaptic stimulation NMDARs regulated p38MAPK in the opposite fashion, causing an increase in intracellular concentration.<ref name="WangBriz2013">{{cite journal | vauthors = Wang Y, Briz V, Chishti A, Bi X, Baudry M | title = Distinct roles for μ-calpain and m-calpain in synaptic NMDAR-mediated neuroprotection and extrasynaptic NMDAR-mediated neurodegeneration | journal = The Journal of Neuroscience | volume = 33 | issue = 48 | pages = 18880–18892 | date = November 2013 | pmid = 24285894 | pmc = 3841454 | doi = 10.1523/JNEUROSCI.3293-13.2013 }}</ref><ref name="pmid19625523">{{cite journal | vauthors = Xu J, Kurup P, Zhang Y, Goebel-Goody SM, Wu PH, Hawasli AH, Baum ML, Bibb JA, Lombroso PJ | display-authors = 6 | title = Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP | journal = The Journal of Neuroscience | volume = 29 | issue = 29 | pages = 9330–9343 | date = July 2009 | pmid = 19625523 | pmc = 2737362 | doi = 10.1523/JNEUROSCI.2212-09.2009 }}</ref> Experiments of this type have since been repeated with the results indicating these differences stretch across many pathways linked to cell survival and excitotoxicity.<ref name=":0" />

Two specific proteins have been identified as a major pathway responsible for these different cellular responses [[extracellular signal-regulated kinases|ERK1/2]], and Jacob.<ref name=":0" /> ERK1/2 is responsible for phosphorylation of Jacob when excited by synaptic NMDARs. This information is then [[Nuclear transport|transported to the nucleus]]. Phosphorylation of Jacob does not take place with extrasynaptic NMDA stimulation. This allows the [[transcription factor]]s in the nucleus to respond differently based in the phosphorylation state of Jacob.<ref name="KarpovaMikhaylova2013">{{cite journal | vauthors = Karpova A, Mikhaylova M, Bera S, Bär J, Reddy PP, Behnisch T, Rankovic V, Spilker C, Bethge P, Sahin J, Kaushik R, Zuschratter W, Kähne T, Naumann M, Gundelfinger ED, Kreutz MR | display-authors = 6 | title = Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus | journal = Cell | volume = 152 | issue = 5 | pages = 1119–1133 | date = February 2013 | pmid = 23452857 | doi = 10.1016/j.cell.2013.02.002 | doi-access = free }}</ref>

===Neural plasticity===
NMDA receptors (NMDARs) critically influence the induction of synaptic plasticity. NMDARs trigger both long-term potentiation (LTP) and long-term depression (LTD) via fast synaptic transmission.<ref>{{cite journal | vauthors = Hunt DL, Castillo PE | title = Synaptic plasticity of NMDA receptors: mechanisms and functional implications | journal = Current Opinion in Neurobiology | volume = 22 | issue = 3 | pages = 496–508 | date = June 2012 | pmid = 22325859 | pmc = 3482462 | doi = 10.1016/j.conb.2012.01.007 }}</ref>  Experimental data suggest that extrasynaptic NMDA receptors inhibit LTP while producing LTD.<ref name="pmid21543591">{{cite journal | vauthors = Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ | title = Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors | journal = The Journal of Neuroscience | volume = 31 | issue = 18 | pages = 6627–6638 | date = May 2011 | pmid = 21543591 | pmc = 3100898 | doi = 10.1523/JNEUROSCI.0203-11.2011 }}</ref> Inhibition of LTP can be prevented with the introduction of a [[NMDA receptor antagonist|NMDA antagonist]].<ref name=":0" /> A [[Transcranial magnetic stimulation|theta burst stimulation]] that usually induces LTP with synaptic NMDARs, when applied selectively to extrasynaptic NMDARs produces a LTD.<ref name="LiuYang2013">{{cite journal | vauthors = Liu DD, Yang Q, Li ST | title = Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons | journal = Brain Research Bulletin | volume = 93 | pages = 10–16 | date = April 2013 | pmid = 23270879 | doi = 10.1016/j.brainresbull.2012.12.003 | s2cid = 7836184 }}</ref> Experimentation also indicates that extrasynaptic activity is not required for the formation of LTP. In addition, both synaptic and extrasynaptic activity are involved in expressing a full LTD.<ref name="PapouinLadépêche2012">{{cite journal | vauthors = Papouin T, Ladépêche L, Ruel J, Sacchi S, Labasque M, Hanini M, Groc L, Pollegioni L, Mothet JP, Oliet SH | display-authors = 6 | title = Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists | journal = Cell | volume = 150 | issue = 3 | pages = 633–646 | date = August 2012 | pmid = 22863013 | doi = 10.1016/j.cell.2012.06.029 | doi-access = free | hdl = 11383/1788727 | hdl-access = free }}</ref>

===Role of differing subunits===
Another factor that seems to affect NMDAR induced toxicity is the observed variation in [[Protein subunit|subunit]] makeup. NMDA receptors are heterotetramers with two GluN1 subunits and two variable subunits.<ref name=":0" /><ref>{{cite journal | vauthors = Sanz-Clemente A, Nicoll RA, Roche KW | title = Diversity in NMDA receptor composition: many regulators, many consequences | journal = The Neuroscientist | volume = 19 | issue = 1 | pages = 62–75 | date = February 2013 | pmid = 22343826 | pmc = 3567917 | doi = 10.1177/1073858411435129 }}</ref> Two of these variable subunits, GluN2A and GluN2B, have been shown to preferentially lead to cell survival and cell death cascades respectively. Although both subunits are found in synaptic and extrasynaptic NMDARs there is some evidence to suggest that the GluN2B subunit occurs more frequently in extrasynaptic receptors. This observation could help explain the dualistic role that NMDA receptors play in excitotoxicity.<ref name="pmid20096331">{{cite journal | vauthors = Petralia RS, Wang YX, Hua F, Yi Z, Zhou A, Ge L, Stephenson FA, Wenthold RJ | display-authors = 6 | title = Organization of NMDA receptors at extrasynaptic locations | journal = Neuroscience | volume = 167 | issue = 1 | pages = 68–87 | date = April 2010 | pmid = 20096331 | pmc = 2840201 | doi = 10.1016/j.neuroscience.2010.01.022 }}</ref><ref name="pmid21310659">{{cite journal | vauthors = Lai TW, Shyu WC, Wang YT | title = Stroke intervention pathways: NMDA receptors and beyond | journal = Trends in Molecular Medicine | volume = 17 | issue = 5 | pages = 266–275 | date = May 2011 | pmid = 21310659 | doi = 10.1016/j.molmed.2010.12.008 }}</ref> t-NMDA receptors have been implicated in excitotoxicity-mediated death of neurons in [[temporal lobe epilepsy]].<ref name=":3">{{cite journal | vauthors = Beesley S, Sullenberger T, Crotty K, Ailani R, D'Orio C, Evans K, Ogunkunle EO, Roper MG, Kumar SS | display-authors = 6 | title = D-serine mitigates cell loss associated with temporal lobe epilepsy | journal = Nature Communications | volume = 11 | issue = 1 | pages = 4966 | date = October 2020 | pmid = 33009404 | pmc = 7532172 | doi = 10.1038/s41467-020-18757-2 | bibcode = 2020NatCo..11.4966B }}</ref>

Despite the compelling evidence and the relative simplicity of these two theories working in tandem, there is still disagreement about the significance of these claims. Some problems in proving these theories arise with the difficulty of using pharmacological means to determine the subtypes of specific NMDARs.<ref name=":0">{{cite journal | vauthors = Parsons MP, Raymond LA | title = Extrasynaptic NMDA receptor involvement in central nervous system disorders | journal = Neuron | volume = 82 | issue = 2 | pages = 279–293 | date = April 2014 | pmid = 24742457 | doi = 10.1016/j.neuron.2014.03.030 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Fourie C, Li D, Montgomery JM | title = The anchoring protein SAP97 influences the trafficking and localisation of multiple membrane channels | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1838 | issue = 2 | pages = 589–594 | date = February 2014 | pmid = 23535319 | doi = 10.1016/j.bbamem.2013.03.015 | doi-access = free }}</ref> In addition, the theory of subunit variation does not explain how this effect might predominate, as it is widely held that the most common tetramer, made from two GluN1 subunits and one of each subunit GluN2A and GluN2B, makes up a high percentage of the NMDARs.<ref name=":0" /> The subunit composition of ''t''-NMDA receptors has recently been visualized in brain tissue.<ref>{{cite journal | vauthors = Beesley S, Gunjan A, Kumar SS | title = Visualizing the triheteromeric N-methyl-D-aspartate receptor subunit composition | journal = Frontiers in Synaptic Neuroscience | volume = 15 | pages = 1156777 | date = 2023 | pmid = 37292368 | pmc = 10244591 | doi = 10.3389/fnsyn.2023.1156777 | doi-access = free }}</ref>

===Excitotoxicity in a clinical setting===
Excitotoxicity has been thought to play a role in the degenerative properties of [[Neurodegeneration|neurodegenerative]] conditions since the late 1950s.<ref>{{cite journal | vauthors = Lucas DR, Newhouse JP | title = The toxic effect of sodium L-glutamate on the inner layers of the retina | journal = A.M.A. Archives of Ophthalmology | volume = 58 | issue = 2 | pages = 193–201 | date = August 1957 | pmid = 13443577 | doi = 10.1001/archopht.1957.00940010205006 }}</ref> NMDA receptors seem to play an important role in many of these degenerative diseases affecting the brain. Most notably, excitotoxic events involving NMDA receptors have been linked to Alzheimer's disease and Huntington's disease, as well as with other medical conditions such as strokes and epilepsy.<ref name=":0" /><ref name="pmid20152125">{{cite journal | vauthors = Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines RM, Boyd JD, Ko RW, Vasuta OC, Graham RK, Hayden MR, Murphy TH, Raymond LA | display-authors = 6 | title = Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice | journal = Neuron | volume = 65 | issue = 2 | pages = 178–190 | date = January 2010 | pmid = 20152125 | doi = 10.1016/j.neuron.2010.01.008 | s2cid = 12987037 | doi-access = free }}</ref> Treating these conditions with one of the many known NMDA receptor antagonists, however, leads to a variety of unwanted side effects, some of which can be severe. These side effects are, in part, observed because the NMDA receptors do not just signal for cell death but also play an important role in its vitality.<ref name=":2" /> Treatment for these conditions might be found in blocking NMDA receptors not found at the synapse.<ref name=":0" /><ref name=":4"/> One class of excitotoxicity in disease includes gain-of-function mutations in GRIN2B and GRIN1 associated with cortical malformations, such as [[polymicrogyria]].<ref>{{cite journal | vauthors = Smith RS, Walsh CA | title = Ion Channel Functions in Early Brain Development | journal = Trends in Neurosciences | volume = 43 | issue = 2 | pages = 103–114 | date = February 2020 | pmid = 31959360 | pmc = 7092371 | doi = 10.1016/j.tins.2019.12.004 }}</ref> D-serine, an antagonist/inverse co-agonist of ''t''-NMDA receptors, which is made in the brain, has been shown to mitigate neuron loss in an animal model of [[temporal lobe epilepsy]].<ref name=":3" />

==Ligands==

===Agonists===
[[Image:L-Glutaminsäure - L-Glutamic_acid.svg|thumb|right|200px|<small>L</small>-[[Glutamic acid]] (glutamate), the major endogenous agonist of the main site of the NMDAR]]
[[Image:Glycine-2D-skeletal.svg|thumb|right|150px|[[Glycine]], the major endogenous agonist of the glycine co-agonist site of the NMDAR]]

Activation of NMDA receptors requires binding of [[glutamic acid|glutamate]] or [[aspartic acid|aspartate]] (aspartate does not stimulate the receptors as strongly).<ref name="pmid15703381">{{cite journal | vauthors = Chen PE, Geballe MT, Stansfeld PJ, Johnston AR, Yuan H, Jacob AL, Snyder JP, Traynelis SF, Wyllie DJ | display-authors = 6 | title = Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling | journal = Molecular Pharmacology | volume = 67 | issue = 5 | pages = 1470–1484 | date = May 2005 | pmid = 15703381 | doi = 10.1124/mol.104.008185 | s2cid = 13505187 }}</ref> In addition, NMDARs also require the binding of the [[co-agonist]] [[glycine]] for the efficient opening of the ion channel, which is a part of this receptor.

[[D-Serine|<small>D</small>-Serine]] has also been found to co-agonize the NMDA receptor with even greater potency than glycine.<ref name="pmid17033043">{{cite journal | vauthors = Wolosker H | title = D-serine regulation of NMDA receptor activity | journal = Science's STKE | volume = 2006 | issue = 356 | pages = pe41 | date = October 2006 | pmid = 17033043 | doi = 10.1126/stke.3562006pe41 | s2cid = 39125762 }}</ref> It is produced by [[serine racemase]], and is enriched in the same areas as NMDA receptors. Removal of <small>D</small>-serine can block NMDA-mediated excitatory neurotransmission in many areas. Recently, it has been shown that <small>D</small>-serine can be released both by neurons and astrocytes to regulate NMDA receptors. Note that D-serine has also been shown to work as an antagonist / inverse co-agonist for ''t''-NMDA receptors.<ref name=":6">{{cite journal | vauthors = Beesley S, Kumar SS | title = The t-N-methyl-d-aspartate receptor: Making the case for d-Serine to be considered its inverse co-agonist | journal = Neuropharmacology | volume = 238 | pages = 109654 | date = November 2023 | pmid = 37437688 | doi = 10.1016/j.neuropharm.2023.109654 | doi-access = free }}</ref><ref name=":3" />

NMDA receptor (NMDAR)-mediated currents are directly related to membrane depolarization. NMDA agonists therefore exhibit fast [[Mg ion (physiology)|Mg<sup>2+</sup>]] unbinding kinetics, increasing channel open probability with depolarization. This property is fundamental to the role of the NMDA receptor in [[memory]] and [[learning]], and it has been suggested that this channel is a biochemical substrate of [[Hebbian learning]], where it can act as a coincidence detector for membrane depolarization and synaptic transmission.

====Examples====
Some known NMDA receptor agonists include:
* [[Amino acid]]s and amino acid derivatives
** [[Aspartic acid]] (aspartate) ([[aspartic acid|<small>D</small>-aspartic acid]], [[aspartic acid|<small>L</small>-aspartic acid]]) – endogenous glutamate site agonist. The word ''N''-methyl-<small>D</small>-aspartate (NMDA) is partially derived from <small>D</small>-aspartate.
** [[Glutamic acid]] (glutamate) – endogenous glutamate site agonist
*** [[Tetrazolylglycine]] – synthetic glutamate site agonist
*** [[Homocysteic acid]] – endogenous glutamate site agonist
*** [[Ibotenic acid]] – naturally occurring glutamate site agonist found in ''[[Amanita muscaria]]''
*** [[Quinolinic acid]] (quinolinate) – endogenous glutamate site agonist
** [[Glycine]] – endogenous glycine site agonist
*** [[Alanine]] ([[alanine|<small>D</small>-alanine]], [[alanine|<small>L</small>-alanine]]) – endogenous glycine site agonist
*** [[Milacemide]] – synthetic glycine site agonist; prodrug of [[glycine]]
*** [[Sarcosine]] (monomethylglycine) – endogenous glycine site agonist
*** [[Serine]] ([[serine|<small>D</small>-serine]], [[serine|<small>L</small>-serine]]) – endogenous glycine site agonist
* [[Positive allosteric modulator]]s
** [[Cerebrosterol]] – endogenous weak positive allosteric modulator
** [[Cholesterol]] – endogenous weak positive allosteric modulator
** [[Dehydroepiandrosterone]] (DHEA) – endogenous weak positive allosteric modulator
** [[Dehydroepiandrosterone sulfate]] (DHEA-S) – endogenous weak positive allosteric modulator
** [[Nebostinel]] (neboglamine) – synthetic positive allosteric modulator of the glycine site
** [[Pregnenolone sulfate]] – endogenous weak positive allosteric modulator
* Polyamines
** [[Spermidine]] – endogenous polyamine site agonist
** [[Spermine]] – endogenous polyamine site agonist

==== Neramexane ====
[[File:Neramexane.svg|thumb|right|'''Figure 6:''' Chemical structure of neramexane, second generation memantine derivative]]
An example of memantine derivative is [[neramexane]] which was discovered by studying number of aminoalkyl [[cyclohexanes]], with memantine as the template, as NMDA receptor antagonists. Neramexane binds to the same site as memantine within the NMDA receptor associated channel and with comparable affinity. It does also show very similar bioavailability and blocking kinetics [[in vivo]] as memantine. Neramexane went to [[clinical trials]] for four indications, including Alzheimer's disease.<ref name="Wanka" />

===Partial agonists===
[[Image:NMDA.svg|thumb|right|200px|[[N-Methyl-D-aspartic acid|''N''-Methyl-<small>D</small>-aspartic acid]] (NMDA), a synthetic partial agonist of the main site of the NMDAR]]

[[N-Methyl-D-aspartic acid|''N''-Methyl-<small>D</small>-aspartic acid]] (NMDA), which the NMDA receptor was named after, is a partial agonist of the active or glutamate recognition site.

3,5-Dibromo-<small>L</small>-phenylalanine, a naturally occurring halogenated derivative of [[Phenylalanine|<small>L</small>-phenylalanine]], is a weak partial NMDA receptor agonist acting on the glycine site.<ref>{{cite journal | vauthors = Yarotskyy V, Glushakov AV, Sumners C, Gravenstein N, Dennis DM, Seubert CN, Martynyuk AE | title = Differential modulation of glutamatergic transmission by 3,5-dibromo-L-phenylalanine | journal = Molecular Pharmacology | volume = 67 | issue = 5 | pages = 1648–1654 | date = May 2005 | pmid = 15687225 | doi = 10.1124/mol.104.005983 | s2cid = 11672391 }}</ref><ref>{{Cite journal |last1=Kagiyama |first1=Tomoko |last2=Glushakov |first2=Alexander V. |last3=Sumners |first3=Colin |last4=Roose |first4=Brandy |last5=Dennis |first5=Donn M. |last6=Phillips |first6=M. Ian |last7=Ozcan |first7=Mehmet S. |last8=Seubert |first8=Christoph N. |last9=Martynyuk |first9=Anatoly E. |date=April 8, 2004 |title=Neuroprotective Action of Halogenated Derivatives of L-Phenylalanine |url=https://www.ahajournals.org/doi/10.1161/01.str.0000125722.10606.07 |journal=Stroke |volume=35 |issue=5 |pages=1192–1196 |doi=10.1161/01.STR.0000125722.10606.07|pmid=15073406 |url-access=subscription }}</ref> 3,5-Dibromo-<small>L</small>-phenylalanine has been proposed a novel therapeutic drug candidate for treatment of neuropsychiatric disorders and diseases such as [[schizophrenia]],<ref>{{cite journal | vauthors = Martynyuk AE, Seubert CN, Yarotskyy V, Glushakov AV, Gravenstein N, Sumners C, Dennis DM | title = Halogenated derivatives of aromatic amino acids exhibit balanced antiglutamatergic actions: potential applications for the treatment of neurological and neuropsychiatric disorders | journal = Recent Patents on CNS Drug Discovery | volume = 1 | issue = 3 | pages = 261–270 | date = November 2006 | pmid = 18221208 | doi = 10.2174/157488906778773706 }}</ref> and neurological disorders such as [[ischemic stroke]] and [[epileptic seizure]]s.<ref>{{cite journal | vauthors = Cao W, Shah HP, Glushakov AV, Mecca AP, Shi P, Sumners C, Seubert CN, Martynyuk AE | display-authors = 6 | title = Efficacy of 3,5-dibromo-L-phenylalanine in rat models of stroke, seizures and sensorimotor gating deficit | journal = British Journal of Pharmacology | volume = 158 | issue = 8 | pages = 2005–2013 | date = December 2009 | pmid = 20050189 | pmc = 2807662 | doi = 10.1111/j.1476-5381.2009.00498.x }}</ref>

Other partial agonists of the NMDA receptor acting on novel sites such as [[rapastinel]] (GLYX-13) and [[apimostinel]] (NRX-1074) are now viewed for the development of new drugs with antidepressant and analgesic effects without obvious psychotomimetic activities.<ref>J. Moskal, D. Leander, R. Burch (2010). Unlocking the Therapeutic Potential of the NMDA Receptor. [http://www.dddmag.com/articles/2010/10/unlocking-therapeutic-potential-nmda-receptor ''Drug Discovery & Development News''.] Retrieved 19 December 2013.</ref>

====Examples====
* [[Aminocyclopropanecarboxylic acid]] (ACC) – synthetic glycine site partial agonist
* [[Cycloserine]] ([[D-cycloserine|<small>D</small>-cycloserine]]) – naturally occurring glycine site partial agonist found in ''[[Streptomyces|Streptomyces orchidaceus]]''
* [[HA-966]] and [[L-687,414]] – synthetic glycine site weak partial agonists
* [[Homoquinolinic acid]] – synthetic glutamate site partial agonist
* [[N-Methyl-D-aspartic acid|''N''-Methyl-<small>D</small>-aspartic acid]] (NMDA) – synthetic glutamate site partial agonist

Positive allosteric modulators include:
* [[AGN-241751|Zelquistinel]] (GATE-251) – synthetic novel site partial agonist
* [[Apimostinel]] (GATE-202) – synthetic novel site partial agonist
* [[Rapastinel]] (GLYX-13) – synthetic novel site partial agonist<ref>{{cite journal | vauthors = Donello JE, Banerjee P, Li YX, Guo YX, Yoshitake T, Zhang XL, Miry O, Kehr J, Stanton PK, Gross AL, Burgdorf JS, Kroes RA, Moskal JR | display-authors = 6 | title = Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects | journal = The International Journal of Neuropsychopharmacology | volume = 22 | issue = 3 | pages = 247–259 | date = March 2019 | pmid = 30544218 | pmc = 6403082 | doi = 10.1093/ijnp/pyy101 }}</ref>

===Antagonists===
{{Main|NMDA receptor antagonist}}
[[Image:Ketamine.svg|thumb|right|150px|[[Ketamine]], a synthetic general anesthetic and one of the best-known NMDAR antagonists]]

Antagonists of the NMDA receptor are used as [[anesthetic]]s for animals and sometimes humans, and are often used as [[recreational drug]]s due to their [[hallucinogenic]] properties, in addition to their unique effects at elevated dosages such as [[dissociation (psychology)|dissociation]]. When certain NMDA receptor antagonists are given to rodents in large doses, they can cause a form of [[brain damage]] called [[Olney's lesions]]. NMDA receptor antagonists that have been shown to induce Olney's lesions include [[ketamine]] and [[phencyclidine]], as well as some NMDA receptor antagonists used only in research environments. So far, the published research on Olney's lesions is inconclusive in its occurrence upon human or monkey brain tissues with respect to an increase in the presence of NMDA receptor antagonists.<ref name="urlErowid DXM Vaults">{{cite web | url = http://www.erowid.org/chemicals/dxm/dxm_health2.shtml | title = The Bad News Isn't In: A Look at Dissociative-Induced Brain Damage and Cognitive Impairment | vauthors = Anderson C | date = 2003-06-01 | work = Erowid DXM Vaults : Health | access-date = 2008-12-17}}</ref>

Most NMDAR antagonists are [[uncompetitive antagonist|uncompetitive]] or [[noncompetitive antagonist|noncompetitive blocker]]s of the channel pore or are antagonists of the glycine co-regulatory site rather than antagonists of the active/glutamate site.

====Examples====
Common agents in which NMDA receptor antagonism is the primary or a major mechanism of action:
* [[4-Chlorokynurenine]] (AV-101) – glycine site antagonist; prodrug of [[7-chlorokynurenic acid]]<ref name="Flight2013">{{cite journal | vauthors = Flight MH | title = Trial watch: phase II boost for glutamate-targeted antidepressants | journal = Nature Reviews. Drug Discovery | volume = 12 | issue = 12 | pages = 897 | date = December 2013 | pmid = 24287771 | doi = 10.1038/nrd4178 | s2cid = 33113283 | doi-access = free }}</ref><ref name="VécseiSzalárdy2012">{{cite journal | vauthors = Vécsei L, Szalárdy L, Fülöp F, Toldi J | title = Kynurenines in the CNS: recent advances and new questions | journal = Nature Reviews. Drug Discovery | volume = 12 | issue = 1 | pages = 64–82 | date = January 2013 | pmid = 23237916 | doi = 10.1038/nrd3793 | s2cid = 31914015 }}</ref>
* [[7-Chlorokynurenic acid]] – glycine site antagonist
* [[Agmatine]] – endogenous polyamine site antagonist<ref name="pmid10785653">{{cite journal | vauthors = Reis DJ, Regunathan S | title = Is agmatine a novel neurotransmitter in brain? | journal = Trends in Pharmacological Sciences | volume = 21 | issue = 5 | pages = 187–193 | date = May 2000 | pmid = 10785653 | doi = 10.1016/s0165-6147(00)01460-7 | doi-access = free }}</ref><ref name="pmid12363406">{{cite journal | vauthors = Gibson DA, Harris BR, Rogers DT, Littleton JM | title = Radioligand binding studies reveal agmatine is a more selective antagonist for a polyamine-site on the NMDA receptor than arcaine or ifenprodil | journal = Brain Research | volume = 952 | issue = 1 | pages = 71–77 | date = October 2002 | pmid = 12363406 | doi = 10.1016/s0006-8993(02)03198-0 | s2cid = 38065910 }}</ref>
* Argiotoxin-636 – naturally occurring dizocilpine or related site antagonist found in ''[[Argiope (spider)|Argiope]]'' venom
* [[AP5]] – glutamate site antagonist
* [[AP-7 (drug)|AP7]] – glutamate site antagonist
* [[CGP-37849]] – glutamate site antagonist
* [[Serine|D-serine]] - ''t''-NMDA receptor antagonist / inverse co-agonist<ref name=":6" /><ref name=":3" />
* [[Delucemine]] (NPS-1506) – dizocilpine or related site antagonist; derived from argiotoxin-636<ref name="pmid11026487">{{cite journal | vauthors = Mueller AL, Artman LD, Balandrin MF, Brady E, Chien Y, DelMar EG, Kierstead A, Marriott TB, Moe ST, Raszkiewicz JL, VanWagenen B, Wells D | display-authors = 6 | title = NPS 1506, a moderate affinity uncompetitive NMDA receptor antagonist: preclinical summary and clinical experience | journal = Amino Acids | volume = 19 | issue = 1 | pages = 177–179 | year = 2000 | pmid = 11026487 | doi = 10.1007/s007260070047 | s2cid = 2899648 }}</ref><ref name="pmid26257776">{{cite journal | vauthors = Monge-Fuentes V, Gomes FM, Campos GA, Silva J, Biolchi AM, Dos Anjos LC, Gonçalves JC, Lopes KS, Mortari MR | display-authors = 6 | title = Neuroactive compounds obtained from arthropod venoms as new therapeutic platforms for the treatment of neurological disorders | journal = The Journal of Venomous Animals and Toxins Including Tropical Diseases | volume = 21 | pages = 31 | year = 2015 | pmid = 26257776 | pmc = 4529710 | doi = 10.1186/s40409-015-0031-x | doi-access = free }}</ref>
* [[Dextromethorphan]] (DXM) – dizocilpine site antagonist; prodrug of [[dextrorphan]]
* [[Dextrorphan]] (DXO) – dizocilpine site antagonist
* [[Dexanabinol]] – dizocilpine-related site antagonist<ref name="ShohamiMechoulam2000">{{cite journal | vauthors = Pop E | title = Nonpsychotropic synthetic cannabinoids | journal = Current Pharmaceutical Design | volume = 6 | issue = 13 | pages = 1347–1360 | date = September 2000 | pmid = 10903397 | doi = 10.2174/1381612003399446 }}</ref><ref name="pmid2556719">{{cite journal | vauthors = Feigenbaum JJ, Bergmann F, Richmond SA, Mechoulam R, Nadler V, Kloog Y, Sokolovsky M | title = Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 23 | pages = 9584–9587 | date = December 1989 | pmid = 2556719 | pmc = 298542 | doi = 10.1073/pnas.86.23.9584 | doi-access = free | bibcode = 1989PNAS...86.9584F }}</ref><ref name="pmid8242387">{{cite journal | vauthors = Nadler V, Mechoulam R, Sokolovsky M | title = Blockade of 45Ca2+ influx through the N-methyl-D-aspartate receptor ion channel by the non-psychoactive cannabinoid HU-211 | journal = Brain Research | volume = 622 | issue = 1–2 | pages = 79–85 | date = September 1993 | pmid = 8242387 | doi = 10.1016/0006-8993(93)90804-v | s2cid = 36689761 }}</ref>
* [[Diethyl ether]] – unknown site antagonist
* [[Diphenidine]] – dizocilpine site antagonist
* [[Dizocilpine]] (MK-801) – dizocilpine site antagonist
* [[Eliprodil]] – ifenprodil site antagonist
* [[Esketamine]] – dizocilpine site antagonist
* [[Hodgkinsine]] – undefined site antagonist
* [[Ifenprodil]] – ifenprodil site antagonist<ref name="pmid21677647">{{cite journal | vauthors = Karakas E, Simorowski N, Furukawa H | title = Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors | journal = Nature | volume = 475 | issue = 7355 | pages = 249–253 | date = June 2011 | pmid = 21677647 | pmc = 3171209 | doi = 10.1038/nature10180 }}</ref>
* [[Kaitocephalin]] – naturally occurring glutamate site antagonist found in ''[[Eupenicillium shearii]]''
* [[Ketamine]] – dizocilpine site antagonist
* [[Kynurenic acid]] – endogenous glycine site antagonist
* [[Lanicemine]] – low-trapping dizocilpine site antagonist
* [[LY-235959]] – glutamate site antagonist
* [[Memantine]] – low-trapping dizocilpine site antagonist
* [[Methoxetamine]] – dizocilpine site antagonist
* [[Midafotel]] – glutamate site antagonist
* [[Nitrous oxide]] (N<sub>2</sub>O) – undefined site antagonist
* [[PEAQX]] – glutamate site antagonist
* [[Perzinfotel]] – glutamate site antagonist
* [[Phencyclidine]] (PCP) – dizocilpine site antagonist
* [[Phenylalanine]] - a naturally occurring amino acid, glycine site antagonist<ref name=pmid11986979>{{cite journal | vauthors = Glushakov AV, Dennis DM, Morey TE, Sumners C, Cucchiara RF, Seubert CN, Martynyuk AE | title = Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria | journal = Molecular Psychiatry | volume = 7 | issue = 4 | pages = 359–367 | year = 2002 | pmid = 11986979 | doi = 10.1038/sj.mp.4000976 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Glushakov AV, Glushakova O, Varshney M, Bajpai LK, Sumners C, Laipis PJ, Embury JE, Baker SP, Otero DH, Dennis DM, Seubert CN, Martynyuk AE | display-authors = 6 | title = Long-term changes in glutamatergic synaptic transmission in phenylketonuria | journal = Brain | volume = 128 | issue = Pt 2 | pages = 300–307 | date = February 2005 | pmid = 15634735 | doi = 10.1093/brain/awh354 | doi-access = free }}</ref>
* [[Psychotridine]] – undefined site antagonist
* [[Selfotel]] – glutamate site antagonist
* [[Tiletamine]] – dizocilpine site antagonist
* [[Traxoprodil]] – ifenprodil site antagonist
* [[Xenon]] – unknown site antagonist

Some common agents in which weak NMDA receptor antagonism is a secondary or additional action include:
* [[Amantadine]] – an [[antiviral]] and [[Management of Parkinson's disease#Medication|antiparkinsonian]] drug; low-trapping dizocilpine site antagonist<ref>{{ClinicalTrialsGov|NCT00188383|Effects of ''N''-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy}}</ref>
* [[Atomoxetine]] – a [[norepinephrine reuptake inhibitor]] used to treat {{abbrlink|ADHD|attention-deficit hyperactivity disorder}}<ref name="Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations">{{cite journal | vauthors = Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O, Weigt HU, Fegert JM, Boeckers TM, Föhr KJ | display-authors = 6 | title = Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations | journal = British Journal of Pharmacology | volume = 160 | issue = 2 | pages = 283–291 | date = May 2010 | pmid = 20423340 | pmc = 2874851 | doi = 10.1111/j.1476-5381.2010.00707.x }}</ref>
* [[Dextropropoxyphene]] – an [[opioid analgesic]]
* [[Ethanol]] ([[alcoholic drink|alcohol]]) – a [[euphoriant]], [[sedative]], and [[anxiolytic]] used recreationally; unknown site antagonist
* [[Guaifenesin]] – an [[expectorant]]
* [[Huperzine A]] – a naturally occurring [[acetylcholinesterase inhibitor]] and potential [[antidementia]] agent
* [[Ibogaine]] – a naturally occurring [[hallucinogen]] and [[antiaddictive]] agent
* [[Ketobemidone]] – an opioid analgesic
* [[Methadone]] – an opioid analgesic
* [[Minocycline]] – an [[antibiotic]]<ref name="pmid28616020">{{cite journal | vauthors = Shultz RB, Zhong Y | title = Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury | journal = Neural Regeneration Research | volume = 12 | issue = 5 | pages = 702–713 | date = May 2017 | pmid = 28616020 | pmc = 5461601 | doi = 10.4103/1673-5374.206633 | doi-access = free }}</ref>
* [[Tramadol]] – an atypical opioid analgesic and [[serotonin releasing agent]]

==== Nitromemantine ====
The NMDA receptor is regulated via [[nitrosylation]] and aminoadamantane can be used as a target-directed shuttle to bring nitrogen oxide (NO) close to the site within the NMDA receptor where it can nitrosylate and regulate the ion channel conductivity.<ref name="Wanka" /> A NO donor that can be used to decrease NMDA receptor activity is the alkyl nitrate nitroglycerin. Unlike many other NO donors, alkyl nitrates do not have potential NO associated [[neurotoxic]] effects. Alkyl nitrates donate NO in the form of a nitro group as seen in figure 7, -NO<sub>2</sub>-, which is a safe donor that avoids neurotoxicity. The nitro group must be targeted to the NMDA receptor, otherwise other effects of NO such as dilatation of blood vessels and consequent [[hypotension]] could result.<ref name="Lipton3" />
[[Nitromemantine]] is a second-generation derivative of memantine, it reduces excitotoxicity mediated by overactivation of the glutamatergic system by blocking NMDA receptor without sacrificing safety. Provisional studies in animal models show that nitromemantines are more effective than memantine as neuroprotectants, both [[in vitro]] and in vivo. Memantine and newer derivatives could become very important weapons in the fight against neuronal damage.<ref name="Lipton1" />
[[File:Nitromemantine.jpg|thumb|center|450px|'''Figure 7:''' Nitroglycerin donate ONO<sub>2</sub> group that leads to second generation memantine analog, [[nitromemantine]]]]

[[Negative allosteric modulator]]s include:
* [[25-Hydroxycholesterol]] – endogenous weak negative allosteric modulator
* [[Conantokin]]s – naturally occurring negative allosteric modulators of the polyamine site found in ''[[Conus geographus]]''<ref name="pmid1328523">{{cite journal | vauthors = Skolnick P, Boje K, Miller R, Pennington M, Maccecchini ML | title = Noncompetitive inhibition of N-methyl-D-aspartate by conantokin-G: evidence for an allosteric interaction at polyamine sites | journal = Journal of Neurochemistry | volume = 59 | issue = 4 | pages = 1516–1521 | date = October 1992 | pmid = 1328523 | doi = 10.1111/j.1471-4159.1992.tb08468.x | s2cid = 25871948 }}</ref>

===Modulators===

====Examples====
The NMDA receptor is modulated by a number of [[endogenous]] and [[exogenous]] compounds:<ref name="pmid15670959">{{cite journal | vauthors = Huggins DJ, Grant GH | title = The function of the amino terminal domain in NMDA receptor modulation | journal = Journal of Molecular Graphics & Modelling | volume = 23 | issue = 4 | pages = 381–388 | date = January 2005 | pmid = 15670959 | doi = 10.1016/j.jmgm.2004.11.006 | bibcode = 2005JMGM...23..381H }}</ref>
* [[Aminoglycoside]]s have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect.
* [[CDK5]] regulates the amount of [[NR2B]]-containing NMDA receptors on the synaptic membrane, thus affecting [[synaptic plasticity]].<ref name="pmid17529984">{{cite journal | vauthors = Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA | display-authors = 6 | title = Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation | journal = Nature Neuroscience | volume = 10 | issue = 7 | pages = 880–886 | date = July 2007 | pmid = 17529984 | pmc = 3910113 | doi = 10.1038/nn1914 }}</ref><ref name="pmid18184784">{{cite journal | vauthors = Zhang S, Edelmann L, Liu J, Crandall JE, Morabito MA | title = Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors | journal = The Journal of Neuroscience | volume = 28 | issue = 2 | pages = 415–424 | date = January 2008 | pmid = 18184784 | pmc = 6670547 | doi = 10.1523/JNEUROSCI.1900-07.2008 }}</ref>
* [[Polyamine]]s do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses.
* [[Reelin]] modulates NMDA function through [[Src Family Kinases|Src family kinases]] and [[DAB1]].<ref name="pmid16148228">{{cite journal | vauthors = Chen Y, Beffert U, Ertunc M, Tang TS, Kavalali ET, Bezprozvanny I, Herz J | title = Reelin modulates NMDA receptor activity in cortical neurons | journal = The Journal of Neuroscience | volume = 25 | issue = 36 | pages = 8209–8216 | date = September 2005 | pmid = 16148228 | pmc = 6725528 | doi = 10.1523/JNEUROSCI.1951-05.2005 }}</ref> significantly enhancing [[Long-term potentiation|LTP]] in the [[hippocampus]].
* [[Src (gene)|Src]] kinase enhances NMDA receptor currents.<ref name="pmid9005855">{{cite journal | vauthors = Yu XM, Askalan R, Keil GJ, Salter MW | title = NMDA channel regulation by channel-associated protein tyrosine kinase Src | journal = Science | volume = 275 | issue = 5300 | pages = 674–678 | date = January 1997 | pmid = 9005855 | doi = 10.1126/science.275.5300.674 | s2cid = 39275755 }}</ref>
* [[Sodium|Na<sup>+</sup>]], [[K ion (physiology)|K<sup>+</sup>]] and [[Ca ion (physiology)|Ca<sup>2+</sup>]] not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors.<ref>{{cite journal | vauthors = Petrozziello T, Boscia F, Tedeschi V, Pannaccione A, de Rosa V, Corvino A, Severino B, Annunziato L, Secondo A | display-authors = 6 | title = Na<sup>+</sup>/Ca<sup>2+</sup> exchanger isoform 1 takes part to the Ca<sup>2+</sup>-related prosurvival pathway of SOD1 in primary motor neurons exposed to beta-methylamino-L-alanine | journal = Cell Communication and Signaling | volume = 20 | issue = 1 | pages = 8 | date = January 2022 | pmid = 35022040 | pmc = 8756626 | doi = 10.1186/s12964-021-00813-z | doi-access = free }}</ref>
* [[Zinc#Biological role|Zn<sup>2+</sup>]] and [[Copper|Cu<sup>2+</sup>]] generally block NMDA current activity in a noncompetitive and a voltage-independent manner. However zinc may potentiate or inhibit the current depending on the neural activity.<ref>{{cite journal | vauthors = Horning MS, Trombley PQ | title = Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms | journal = Journal of Neurophysiology | volume = 86 | issue = 4 | pages = 1652–1660 | date = October 2001 | pmid = 11600628 | doi = 10.1152/jn.2001.86.4.1652 | s2cid = 6141092 }}</ref>
* [[Lead|Pb]]<sup>2+</sup><ref>{{cite journal | vauthors = Neal AP, Stansfield KH, Worley PF, Thompson RE, Guilarte TR | title = Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: potential role of NMDA receptor-dependent BDNF signaling | journal = Toxicological Sciences | volume = 116 | issue = 1 | pages = 249–263 | date = July 2010 | pmid = 20375082 | pmc = 2886862 | doi = 10.1093/toxsci/kfq111 }}</ref> is a potent NMDAR antagonist. Presynaptic deficits resulting from Pb<sup>2+</sup> exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.
* Proteins of the [[major histocompatibility complex]] class I are endogenous negative regulators of NMDAR-mediated currents in the adult hippocampus,<ref name="pmid21135233">{{cite journal | vauthors = Fourgeaud L, Davenport CM, Tyler CM, Cheng TT, Spencer MB, Boulanger LM | title = MHC class I modulates NMDA receptor function and AMPA receptor trafficking | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 51 | pages = 22278–22283 | date = December 2010 | pmid = 21135233 | pmc = 3009822 | doi = 10.1073/pnas.0914064107 | doi-access = free | bibcode = 2010PNAS..10722278F }}</ref> and are required for appropriate NMDAR-induced changes in [[AMPAR]] trafficking <ref name="pmid21135233"/> and NMDAR-dependent [[synaptic plasticity]] and [[learning]] and [[memory]].<ref name="pmid11118151">{{cite journal | vauthors = Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ | title = Functional requirement for class I MHC in CNS development and plasticity | journal = Science | volume = 290 | issue = 5499 | pages = 2155–2159 | date = December 2000 | pmid = 11118151 | pmc = 2175035 | doi = 10.1126/science.290.5499.2155 | bibcode = 2000Sci...290.2155H }}</ref><ref>{{cite journal | vauthors = Nelson PA, Sage JR, Wood SC, Davenport CM, Anagnostaras SG, Boulanger LM | title = MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression | journal = Learning & Memory | volume = 20 | issue = 9 | pages = 505–517 | date = September 2013 | pmid = 23959708 | pmc = 3744042 | doi = 10.1101/lm.031351.113 }}</ref>
* The activity of NMDA receptors is also strikingly sensitive to the changes in [[pH]], and partially inhibited by the ambient concentration of H<sup>+</sup> under physiological conditions.<ref>{{cite journal | vauthors = Traynelis SF, Cull-Candy SG | title = Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons | journal = Nature | volume = 345 | issue = 6273 | pages = 347–350 | date = May 1990 | pmid = 1692970 | doi = 10.1038/345347a0 | s2cid = 4351139 | bibcode = 1990Natur.345..347T }}</ref> The level of inhibition by H<sup>+</sup> is greatly reduced in receptors containing the NR1a subtype, which contains the positively charged insert Exon 5. The effect of this insert may be mimicked by positively charged polyamines and aminoglycosides, explaining their mode of action.
* NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called "redox modulatory site."<ref name="pmid2696504">{{cite journal | vauthors = Aizenman E, Lipton SA, Loring RH | title = Selective modulation of NMDA responses by reduction and oxidation | journal = Neuron | volume = 2 | issue = 3 | pages = 1257–1263 | date = March 1989 | pmid = 2696504 | doi = 10.1016/0896-6273(89)90310-3 | s2cid = 10324716 }}</ref> Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as [[glutathione]], [[lipoic acid]], and the essential nutrient [[pyrroloquinoline quinone]].<ref>{{Cite journal |last1=Aizenman |first1=Elias |last2=Loring |first2=Ralph H. |last3=Reynolds |first3=Ian J. |last4=Rosenberg |first4=Paul A. |date=July 24, 2020 |title=The Redox Biology of Excitotoxic Processes: The NMDA Receptor, TOPA Quinone, and the Oxidative Liberation of Intracellular Zinc |journal=Frontiers in Neuroscience |volume=14 |pages=778 |doi=10.3389/fnins.2020.00778 |doi-access=free |issn=1662-4548 |pmc=7393236 |pmid=32792905}}</ref>

=== Development of NMDA receptor antagonists ===
The main problem with the development of NMDA antagonists for neuroprotection is that physiological NMDA receptor activity is essential for normal neuronal function. Complete blockade of all NMDA receptor activity results in side effects such as [[hallucinations]], agitation and [[anesthesia]]. To be clinically relevant, an NMDA receptor antagonist must limit its action to blockade of excessive activation, without limiting normal function of the receptor.<ref name="Lipton2" />

==== Competitive NMDA receptor antagonists ====
[[Competitive]] NMDA receptor antagonists, which were developed first, are not a good option because they compete and bind to the same site (NR2 subunit) on the receptor as the agonist, glutamate, and therefore block normal function also.<ref name="Lipton2" /><ref name="Monaghan">{{cite book| vauthors = Monaghan DT, Jane DE | veditors = Van Dongen AM |title=Biology of the NMDA Receptor|date=2009|publisher=CRC Press|location=Boca Raton, Florida|isbn=978-1-4200-4414-0|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK5282/|chapter=Pharmacology of NMDA Receptors| series = Frontiers in Neuroscience |pmid=21204415}}</ref> They will block healthy areas of the brain prior to having an impact on pathological areas, because healthy areas contain lower levels of [[agonist]] than pathological areas. These antagonists can be displaced from the receptor by high concentration of glutamate which can exist under excitotoxic circumstances.<ref name="Chen" />

==== Noncompetitive NMDA receptor antagonists ====
[[File:NMDA receptor antagonist.jpg|thumb|right|200px|'''Figure 4:''' The chemical structures of MK-801, phencyclidine and ketamine, high affinity uncompetitive NMDA receptor antagonists]]
Uncompetitive NMDA receptor antagonists block within the ion channel at the Mg<sup>2+</sup> site (pore region) and prevent excessive influx of Ca<sup>2+</sup>. Noncompetitive antagonism refers to a type of block that an increased concentration of glutamate cannot overcome, and is dependent upon prior activation of the receptor by the agonist, i.e. it only enters the channel when it is opened by agonist.<ref name="Lipton2" /><ref name="Sonkusare">{{cite journal | vauthors = Sonkusare SK, Kaul CL, Ramarao P | title = Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope | journal = Pharmacological Research | volume = 51 | issue = 1 | pages = 1–17 | date = January 2005 | pmid = 15519530 | doi = 10.1016/j.phrs.2004.05.005 }}</ref>

==== Memantine and related compounds ====
[[File:Memantine and amantadine.jpg|thumb|right|300px|'''Figure 5:''' Chemical structures of memantine (right) and amantadine (left)]]
Because of these adverse side effects of high affinity blockers, the search for clinically successful NMDA receptor antagonists for neurodegenerative diseases continued and focused on developing low affinity blockers. However the affinity could not be too low and dwell time not too short (as seen with Mg<sup>2+</sup>) where membrane depolarization relieves the block. The discovery was thereby development of uncompetitive antagonist with longer dwell time than Mg<sup>2+</sup> in the channel but shorter than MK-801. That way the drug obtained would only block excessively open NMDA receptor associated channels but not normal neurotransmission.<ref name="Lipton2" /><ref name="Sonkusare" /> Memantine is that drug. It is a derivative of amantadine which was first an anti-influenza agent but was later discovered by coincidence to have efficacy in Parkinson's disease. Chemical structures of memantine and amantadine can be seen in figure 5. The compound was first thought to be [[dopaminergic]] or [[anticholinergic]] but was later found to be an NMDA receptor antagonist.<ref name="Dominguez" /><ref name="Lipton2" />

Memantine is the first drug approved for treatment of severe and more advanced [[Alzheimer's disease]], which for example anticholinergic drugs do not do much good for.<ref name="Sonkusare" /> It helps recovery of synaptic function and in that way improves impaired memory and learning.<ref name="Koch" /> In 2015 memantine is also in trials for therapeutic importance in additional neurological disorders.<ref name="Lipton3">{{cite journal | vauthors = Lipton SA | title = Pathologically activated therapeutics for neuroprotection | journal = Nature Reviews. Neuroscience | volume = 8 | issue = 10 | pages = 803–808 | date = October 2007 | pmid = 17882256 | doi = 10.1038/nrn2229 | s2cid = 34931289 }}</ref>

Many second-generation memantine derivatives have been in development that may show even better neuroprotective effects, where the main thought is to use other safe but effective modulatory sites on the NMDA receptor in addition to its associated ion channel.<ref name="Lipton3" />

=== Structure activity relationship (SAR) ===
[[File:SAR of amantadine and related compunds.jpg|thumb|right|300px|'''Figure 8:''' Structure activity relationship (SAR) of amantadine and related compounds]]

Memantine (1-amino-3,5-dimethyladamantane) is an aminoalkyl cyclohexane derivative and an atypical drug compound with non-planar, three dimensional tricyclic structure. Figure 8 shows SAR for aminoalkyl cyclohexane derivative. Memantine has several important features in its structure for its effectiveness:
* Three-ring structure with a bridgehead amine, -NH<sub>2</sub>
* The -NH<sub>2</sub> group is protonated under physiological pH of the body to carry a positive charge, -NH<sup>3+</sup>
* Two methyl (CH<sub>3</sub>) side groups which serve to prolong the dwell time and increase stability as well as affinity for the NMDA receptor channel compared with amantadine (1-adamantanamine).<ref name="Lipton1" /><ref name="Sonkusare" />

Despite the small structural difference between memantine and amantadine, two adamantane derivatives, the affinity for the binding site of NR1/NR2B subunit is much greater for memantine. In [[patch-clamp]] measurements memantine has an [[IC50|IC<sub>50</sub>]] of (2.3+0.3) μM while amantadine has an IC<sub>50</sub> of (71.0+11.1) μM.<ref name="Wanka" />
The binding site with the highest affinity is called the dominant binding site. It involves a connection between the amine group of memantine and the NR1-N161 binding pocket of the NR1/NR2B subunit. The methyl side groups play an important role in increasing the affinity to the open NMDA receptor channels and making it a much better neuroprotective drug than amantadine. The binding pockets for the methyl groups are considered to be at the NR1-A645 and NR2B-A644 of the NR1/NR2B.<ref name="Limapichat" /> The binding pockets are shown in figure 2.
Memantine binds at or near to the Mg<sup>2+</sup> site inside the NMDA receptor associated channel. The  -NH<sub>2</sub> group on memantine, which is protonated under physiological pH of the body, represents the region that binds at or near to the Mg<sup>2+</sup> site.<ref name="Lipton1" /> Adding two methyl groups to the -N on the memantine structure has shown to decrease affinity, giving an IC<sub>50</sub> value of (28.4+1.4) μM.<ref name="Wanka" />

==== Second generation derivative of memantine; nitromemantine ====
Several derivatives of Nitromemantine, a second-generation derivative of memantine, have been synthesized in order to perform a detailed [[structure activity relationship]] (SAR) of these novel drugs. One class, containing a nitro (NO<sub>2</sub>) group opposite to the bridgehead amine (NH<sub>2</sub>), showed a promising outcome. Nitromemantine utilizes memantine binding site on the NMDA receptor to target the NO<sub>x</sub> (X= 1 or 2) group for interaction with the S- nitrosylation/redox site external to the memantine binding site. Lengthening the side chains of memantine compensates for the worse drug affinity in the channel associated with the addition of the –ONO<sub>2</sub> group<ref name="Takahashi">{{cite journal | vauthors = Takahashi H, Xia P, Cui J, Talantova M, Bodhinathan K, Li W, Saleem S, Holland EA, Tong G, Piña-Crespo J, Zhang D, Nakanishi N, Larrick JW, McKercher SR, Nakamura T, Wang Y, Lipton SA | display-authors = 6 | title = Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease | journal = Scientific Reports | volume = 5 | pages = 14781 | date = October 2015 | pmid = 26477507 | pmc = 4609936 | doi = 10.1038/srep14781 | bibcode = 2015NatSR...514781T }}</ref>

=== Therapeutic application ===
Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and [[amyotrophic lateral sclerosis]].<ref name="Chen" /><ref name="Kemp" /><ref name="Lipton1" /><ref name="Koch" /> Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.<ref name="Chen" /><ref name="Kemp" /><ref name="Lipton1" /> It is, however, important to preserve physiological NMDA receptor activity while trying to block its excessive, excitotoxic activity. This can possibly be achieved by uncompetitive antagonists, blocking the receptor's ion channel when excessively open <ref name="Lipton1" />

Memantine is an example of uncompetitive NMDA receptor antagonist that has approved indication for the neurodegenerative disease Alzheimer's disease. In 2015 memantine is still in clinical trials for additional neurological diseases.<ref name="Limapichat" /><ref name="Lipton3" />

==Receptor modulation==
The NMDA receptor is a non-specific cation channel that can allow the passage of Ca<sup>2+</sup> and Na<sup>+</sup> into the cell and K<sup>+</sup> out of the cell. The [[excitatory postsynaptic potential]] (EPSP) produced by activation of an NMDA receptor increases the concentration of Ca<sup>2+</sup> in the cell. The Ca<sup>2+</sup> can in turn function as a [[second messenger]] in various [[signaling pathway]]s. However, the NMDA receptor cation channel is blocked by Mg<sup>2+</sup> at resting membrane potential.<ref name="Purves129-131">{{cite book | vauthors = Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia AS, McNamara JD, White LE |title=Neuroscience | edition = 4th |publisher=Sinauer Associates |pages=129–131 |year=2008 |isbn=978-0-87893-697-7 |url=http://www.sinauer.com/neuroscience4e |url-status=dead |archive-url=https://web.archive.org/web/20110927082419/http://www.sinauer.com/neuroscience4e/ |archive-date=2011-09-27 }}</ref> Magnesium unblock is not instantaneous; to unblock all available channels, the postsynaptic cell must be depolarized for a sufficiently long period of time (in the scale of milliseconds).<ref name=Vargas-Caballero>{{cite journal | vauthors = Vargas-Caballero M, Robinson HP | title = Fast and slow voltage-dependent dynamics of magnesium block in the NMDA receptor: the asymmetric trapping block model | journal = The Journal of Neuroscience | volume = 24 | issue = 27 | pages = 6171–6180 | date = July 2004 | pmid = 15240809 | pmc = 6729657 | doi = 10.1523/jneurosci.1380-04.2004 }}</ref>

Therefore, the NMDA receptor functions as a "molecular [[Coincidence detection in neurobiology|coincidence detector]]". Its ion channel opens only when the following two conditions are met: glutamate is bound to the receptor, and the postsynaptic cell is depolarized (which removes the Mg<sup>2+</sup> blocking the channel). This property of the NMDA receptor explains many aspects of [[long-term potentiation]] (LTP) and [[synaptic plasticity]].<ref name="Purves191-195">{{cite book | vauthors = Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia AS, McNamara JD, White LE  |title=Neuroscience | edition = 4th |publisher=Sinauer Associates |pages=191–195 |year=2008 |isbn=978-0-87893-697-7 |url=http://www.sinauer.com/neuroscience4e |url-status=dead |archive-url=https://web.archive.org/web/20110927082419/http://www.sinauer.com/neuroscience4e/ |archive-date=2011-09-27 }}</ref>

In a [[Resting membrane potential|resting-membrane potential]], the NMDA receptor pore is opened allowing for an influx of external magnesium ions binding to prevent further ion permeation.<ref>{{cite journal | vauthors = Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A | title = Magnesium gates glutamate-activated channels in mouse central neurones | journal = Nature | volume = 307 | issue = 5950 | pages = 462–465 | date = February 1984 | pmid = 6320006 | doi = 10.1038/307462a0 | bibcode = 1984Natur.307..462N | s2cid = 4344173 }}</ref> External magnesium ions are in a [[millimolar]] range while intracellular magnesium ions are at a [[micromolar]] range to result in negative membrane potential. NMDA receptors are modulated by a number of [[endogenous]] and [[exogenous]] compounds and play a key role in a wide range of [[physiology|physiological]] (e.g., [[memory]]) and [[pathology|pathological]] processes (e.g., [[excitotoxicity]]). Magnesium works to potentiate NMDA-induced responses at positive membrane potentials while blocking the NMDA channel. The use of calcium, potassium, and sodium are used to modulate the activity of NMDARs passing through the NMDA membrane. Changes in H<sup>+</sup> concentration can partially inhibit the activity of NMDA receptors in different physiological conditions.

==Clinical significance==
NMDAR antagonists like [[ketamine]], [[esketamine]], [[tiletamine]], [[phencyclidine]], [[nitrous oxide]], and [[xenon]] are used as [[general anesthetic]]s. These and similar drugs like [[dextromethorphan]] and [[methoxetamine]] also produce [[dissociative drug|dissociative]], [[hallucinogen]]ic, and [[euphoriant]] effects and are used as [[recreational drug]]s.

NMDAR-targeted compounds, including ketamine, [[esketamine]] (JNJ-54135419), [[rapastinel]] (GLYX-13), [[apimostinel]] (NRX-1074), [[AGN-241751|zelquistinel]] (AGN-241751), [[4-chlorokynurenine]] (AV-101), and [[rislenemdaz]] (CERC-301, MK-0657), are under development for the treatment of [[mood disorder]]s, including [[major depressive disorder]] and [[treatment-resistant depression]].<ref name="Flight2013" /><ref name="VécseiSzalárdy2012" /><ref name="issn2168-9709">{{cite journal | vauthors = Wijesinghe R | year = 2014 | title = Emerging Therapies for Treatment Resistant Depression | journal = Ment Health Clin | volume = 4 | issue = 5 | page = 56 | issn = 2168-9709| doi = 10.9740/mhc.n207179 | doi-access = free }}</ref> In addition, ketamine is already employed for this purpose as an off-label therapy in some clinics.<ref name="NPR2014">{{cite web | url = https://www.npr.org/blogs/health/2014/04/03/298770933/growing-evidence-that-a-party-drug-can-help-severe-depression | vauthors = Poon L | title = Growing Evidence That A Party Drug Can Help Severe Depression | publisher = NPR | year = 2014}}</ref><ref name="ScientificAmerican2013">{{cite web | url = http://blogs.scientificamerican.com/talking-back/2013/09/11/from-club-to-clinic-physicians-push-off-label-ketamine-as-rapid-depression-treatment-part-1/ | vauthors = Stix G | title = From Club to Clinic: Physicians Push Off-Label Ketamine as Rapid Depression Treatment | publisher = Scientific American | year = 2014}}</ref>

Research suggests that [[tianeptine]] produces antidepressant effects through indirect alteration and inhibition of [[Glutamate (neurotransmitter)|glutamate]] receptor activity and release of {{abbrlink|BDNF|brain-derived neurotrophic factor}}, in turn affecting [[neural plasticity]].<ref name="mp092">{{cite journal | vauthors = McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, Fuchs E | title = The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation | journal = Molecular Psychiatry | volume = 15 | issue = 3 | pages = 237–249 | date = March 2010 | pmid = 19704408 | pmc = 2902200 | doi = 10.1038/mp.2009.80 }}</ref><ref name="pmid15550348">{{cite journal | vauthors = McEwen BS, Chattarji S | title = Molecular mechanisms of neuroplasticity and pharmacological implications: the example of tianeptine | journal = European Neuropsychopharmacology | volume = 14 | issue = Suppl 5 | pages = S497–S502 | date = December 2004 | pmid = 15550348 | doi = 10.1016/j.euroneuro.2004.09.008 | s2cid = 21953270 }}</ref><ref name="pmid15753957">{{cite journal | vauthors = McEwen BS, Olié JP | title = Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine | journal = Molecular Psychiatry | volume = 10 | issue = 6 | pages = 525–537 | date = June 2005 | pmid = 15753957 | doi = 10.1038/sj.mp.4001648 | doi-access = free }}</ref><ref name="pmid18221189">{{cite journal | vauthors = Brink CB, Harvey BH, Brand L | title = Tianeptine: a novel atypical antidepressant that may provide new insights into the biomolecular basis of depression | journal = Recent Patents on CNS Drug Discovery | volume = 1 | issue = 1 | pages = 29–41 | date = January 2006 | pmid = 18221189 | doi = 10.2174/157488906775245327 | url = http://www.bentham-direct.org/pages/content.php?PRN/2006/00000001/00000001/0002PRN.SGM | access-date = 2020-04-12 | url-status = usurped | archive-url = https://archive.today/20130414074312/http://www.bentham-direct.org/pages/content.php?PRN/2006/00000001/00000001/0002PRN.SGM | archive-date = 2013-04-14 | url-access = subscription }}</ref><ref name="CNS20082">{{cite journal | vauthors = Kasper S, McEwen BS | title = Neurobiological and clinical effects of the antidepressant tianeptine | journal = CNS Drugs | volume = 22 | issue = 1 | pages = 15–26 | year = 2008 | pmid = 18072812 | doi = 10.2165/00023210-200822010-00002 | s2cid = 30330824 }}</ref> Tianeptine also acts on the NMDA and [[AMPA receptor]]s.<ref name="mp092"/><ref name="CNS20082"/> In animal models, tianeptine inhibits the pathological stress-induced changes in glutamatergic neurotransmission in the amygdala and hippocampus.

[[Memantine]], a low-trapping NMDAR antagonist, is approved in the [[United States]] and [[Europe]] for the treatment of moderate-to-severe Alzheimer's disease,<ref name=MountC2006>{{cite journal | vauthors = Mount C, Downton C | title = Alzheimer disease: progress or profit? | journal = Nature Medicine | volume = 12 | issue = 7 | pages = 780–784 | date = July 2006 | pmid = 16829947 | doi = 10.1038/nm0706-780 | doi-access = free }}</ref> and has now received a limited recommendation by the UK's [[National Institute for Health and Care Excellence]] for patients who fail other treatment options.<ref name="NICE Guidelines">NICE technology appraisal January 18, 2011 [http://www.nice.org.uk/guidance/index.jsp?action=download&o=52515 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination]</ref>

Cochlear NMDARs are the target of intense research to find pharmacological solutions to treat [[tinnitus]]. NMDARs are associated with a rare [[autoimmune]] disease, [[anti-NMDA receptor encephalitis]] (also known as NMDAR encephalitis<ref>Todd A Hardy, Reddel, Barnett, Palace, Lucchinetti, Weinshenker, Atypical inflammatory demyelinating syndromes of the CNS, The lancet neurology, Volume 15, Issue 9, August 2016, Pages 967-981, doi: https://doi.org/10.1016/S1474-4422(16)30043-6, available at
[https://ora.ox.ac.uk/objects/uuid:49dc3a62-76a4-4b96-9900-a7cd41d5a61a/download_file?file_format=pdf&safe_filename=Atypical%2Binflammatory%2Bdemyelinating%2Bsyndromes%2Bof%2Bthe%2BCNS.pdf&type_of_work=Journal+article]</ref>), that usually occurs due to cross-reactivity of antibodies produced by the immune system against ectopic brain tissues, such as those found in [[teratoma]]. These are known as [[anti-glutamate receptor antibodies]].

Compared to [[dopaminergic]] [[stimulant]]s like [[methamphetamine]], the NMDAR antagonist phencyclidine can produce a wider range of symptoms that resemble schizophrenia in healthy volunteers, in what has led to the [[glutamate hypothesis of schizophrenia]].<ref name="pmid18395805">{{cite journal | vauthors = Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, Grace AA | title = Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia | journal = Trends in Neurosciences | volume = 31 | issue = 5 | pages = 234–242 | date = May 2008 | pmid = 18395805 | pmc = 2680493 | doi = 10.1016/j.tins.2008.02.005 }}</ref> Experiments in which rodents are treated with NMDA receptor antagonist are today the most common model when it comes to testing of novel schizophrenia therapies or exploring the exact mechanism of drugs already approved for treatment of schizophrenia.

NMDAR antagonists, for instance [[eliprodil]], [[gavestinel]], [[licostinel]], and [[selfotel]] have been extensively investigated for the treatment of [[excitotoxicity]]-mediated [[neurotoxicity]] in situations like [[ischemic stroke]] and [[traumatic brain injury]], but were unsuccessful in [[clinical trial]]s used in small doses to avoid sedation, but NMDAR antagonists can block [[Cortical spreading depression|Spreading Depolarizations]] in animals and in patients with brain injury.<ref>{{cite journal | vauthors = Santos E, Olivares-Rivera A, Major S, Sánchez-Porras R, Uhlmann L, Kunzmann K, Zerelles R, Kentar M, Kola V, Aguilera AH, Herrera MG, Lemale CL, Woitzik J, Hartings JA, Sakowitz OW, Unterberg AW, Dreier JP | display-authors = 6 | title = Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study | journal = Critical Care | volume = 23 | issue = 1 | pages = 427 | date = December 2019 | pmid = 31888772 | pmc = 6937792 | doi = 10.1186/s13054-019-2711-3 | doi-access = free }}</ref> This use has not been tested in clinical trials yet.

== See also ==
* [[Ca2+/calmodulin-dependent protein kinase|Calcium/calmodulin-dependent protein kinases]]

== References ==
{{Reflist|30em}}

== External links ==
* {{Commons-inline|Category:N-methyl-D-aspartate receptors|NMDA receptor}}
* [https://web.archive.org/web/20041213040240/http://www.bris.ac.uk/Depts/Synaptic/info/pharmacology/NMDA.html NMDA receptor pharmacology]
* [https://web.archive.org/web/20090120135112/http://www.jneurosci.org/cgi/content/full/16/24/7859 Motor Discoordination Results from Combined Gene Disruption of the NMDA Receptor NR2A and NR2C Subunits, But Not from Single Disruption of the NR2A or NR2C Subunit]
* [https://www.sdbonline.org/sites/fly/hjmuller/nmda1.htm ''Drosophila'' ''NMDA receptor 1'' - The Interactive Fly]

{{Ligand-gated ion channels}}
{{Ionotropic glutamate receptor modulators}}
{{Neuroethology}}
{{Drug design}}

{{DEFAULTSORT:Nmda Receptor}}
[[Category:Cell signaling]]
[[Category:Glutamate (neurotransmitter)]]
[[Category:Ion channels]]
[[Category:Ionotropic glutamate receptors]]
[[Category:Molecular neuroscience]]
[[Category:NMDA receptor antagonists]]